Phthalazine derivatives as pyruvate kinase modulators

Abstract

The present invention provides compounds of formula (Ia): [Formula 1] TIFF2025538980000091.tif27170 and related aspects.

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to compounds and their use in the treatment or prevention of inflammatory diseases, diseases associated with an unwanted immune response, cancer, obesity, diabetic diseases, or blood disorders, as well as related compositions, methods, and intermediate compounds. [Background technology]

[0002] BACKGROUND OF THE INVENTION Pyruvate kinase (PK) is the final, rate-limiting enzyme in glycolysis, catalyzing the conversion of phosphoenolpyruvate (PEP) and ADP to pyruvate and ATP. In mammals, four PK isoforms exist, derived from two separate genes (Alves-Filho et al., 2016). PKL and PKR, the products of the Pklr gene, are expressed in the liver and erythrocytes, respectively. PKM1 and PKM2 are alternatively spliced ​​products of the Pkm gene. PKM1 is expressed in tissues with high energy demands, such as the heart, muscle, and brain, while PKM2 is expressed in embryonic tissues, cancer cells, and normal proliferating cells, such as lymphocytes and intestinal epithelial cells. PKM1 is a constitutively active enzyme, whereas PKM2 is a less active enzyme that depends on allosteric activation by multiple endogenous regulators, such as the upstream glycolytic intermediate fructose-1,6-bisphosphate (FBP). Binding of these allosteric regulators induces a conformational change in PKM2 that promotes tetramerization, resulting in an increase in the final, rate-limiting step of glycolysis. Pyruvate enters the mitochondrial TCA cycle, where it is used to generate ATP by oxidative phosphorylation. In the absence of allosteric activation, PKM2 adopts dimeric or monomeric forms with low enzymatic activity, leading to the accumulation of glycolytic intermediates that meet the demand for biosynthetic precursors in activated or proliferating cells. Dimeric PKM2 can also translocate to the nucleus, where it can further promote aerobic glycolysis and regulate transcriptional activity, acting as a protein kinase that targets transcription factors and histones.

[0003] Cancer cells primarily use glycolysis to generate cellular energy and biosynthetic intermediates (termed the Warburg effect), and PKM2 plays a dominant role in glycolysis to meet the nutritional requirements for cancer cell growth (Chhipa et al., 2018). PKM2 is overexpressed in almost all cancers and has been shown to promote tumor cell proliferation and metastasis. In addition to regulating glycolytic flux, PKM2's non-metabolic roles as a coactivator and protein kinase contribute to tumorigenesis (Dong et al., 2016). PKM2 directly binds to and phosphorylates histone H3, leading to the expression of c-Myc and cyclin D1 and cancer cell proliferation. Activation of the PKM2 tetramer by small molecules could be an attractive cancer treatment to halt tumor growth by interfering with the non-metabolic functions of dimeric PKM2.

[0004] Following activation or inflammatory stimuli, PKM2 is upregulated in many immune cells, including macrophages and T cells (Palsson-McDermott et al., 2020). The non-metabolic role of dimeric PKM2 has been shown to regulate immune responses: PKM2 acts as a transcriptional coactivator for Hif-1α, b-catenin, and STAT3, leading to the expression of pro-inflammatory cytokines such as IL-1β and TNFα. Activation of PKM2 by small molecules to prevent its nuclear translocation may have therapeutic benefit in various inflammatory and autoimmune diseases, such as rheumatoid arthritis, inflammatory bowel disease, inflammatory skin lesions, coronary artery disease, and multiple sclerosis.

[0005] In diabetes, PKM2 regulates glucose-responsive pancreatic beta-cell function and prevents metabolic stress (Abulizi et al., 2020; Lewandowski et al., 2020). Dimeric PKM2 plays a role in abnormal glycolysis by promoting HIF-1α accumulation. In diabetic nephropathy, PKM2 has been associated with a pathogenic role in glomerular injury and epithelial-mesenchymal transition leading to fibrosis (Liu et al., 2020). PKM2 activation has been shown to amplify insulin release, improve insulin sensitivity, and prevent the progression of diabetic glomerular pathology and renal fibrosis (Liu et al., 2020; Abulizi et al., 2020; Lewandowski et al., 2020; Qi et al., 2017).

[0006] Obesity is defined as abnormal or excessive adiposity that poses a health risk and is associated with a high incidence of type 2 diabetes and cardiovascular disease. This metabolic disorder is strongly associated with insulin resistance and adverse effects on glucose metabolism and processing in obese subjects (Barazzoni et al., 2018). Studies on 3T3-L1 adipocytes exposed to various levels of insulin resulted in a significant increase in PKM2 mRNA levels, independent of the level of glucose in the culture medium (Puckett et al., 2021). Studies on the effects of altered PKM2 phosphorylation status and the resulting decrease in catalytic activity have identified PKM2 as a potential contributor to insulin resistance in adipose tissue and linked it to metabolic conditions in humans (Bettaieb et al., 2013). Restoring PKM2 activity with small molecule allosteric activators has been shown to improve insulin sensitivity (Abulizi 2020; Lewandowski 2020), justifying further consideration as a novel target for pharmacological intervention in obesity.

[0007] Pyruvate kinase deficiency (PKD) is one of the most common enzyme defects in red blood cells, manifesting as hemolytic anemia, the accelerated destruction of red blood cells (Bianchi et al., 2020). Mature red blood cells are entirely dependent on glycolysis to maintain cellular integrity and function, and pyruvate kinase therefore plays a crucial role in red blood cell metabolism and survival. Inherited mutations in the PKR enzyme result in dysregulation of its catalytic activity, causing cellular energy deficits within red blood cells, as evidenced by lower pyruvate kinase enzyme activity, reduced ATP levels, and accumulation of upstream metabolites. Decreased PKR activity is also associated with changes in red blood cell morphology and cell membrane surface, suggesting a broader involvement of this enzyme in the overall lifespan of these cells (Cancado et al., 2018). PK-deficient red blood cells are prematurely removed from the circulation by the spleen through accelerated hemolysis, leading to iron accumulation. Increasing and / or restoring PKR activity to subbasal levels is believed to have the potential to treat complications associated with PK deficiency. The current standard of care for PKD is supportive, including blood transfusions, splenectomy, chelation therapy to address iron overload, and / or other treatments and interventions for disease-related morbidity. There are no approved therapies to treat the underlying cause of PK deficiency. Activation of the PKR enzyme by small molecule allosteric activators increased PK enzyme activity and enhanced glycolysis in red blood cells from patients with PK deficiency (Kung et al., 2017).

[0008] Pharmacological intervention using small molecule agonists such as TEPP-46 and DASA-58 has been widely utilized in in vitro and in vivo biological settings to demonstrate several potential benefits offered by enhancing PK activity through allosteric modulation (Yi et al., 2021). Although these compounds exhibit good levels of in vitro activity, their ADME and pharmacokinetic / pharmacodynamic profiles have prevented their development for the treatment of human diseases. The structure of TEPP-46 is as follows: [ka] .

[0009] The most advanced PK activator being widely tested in clinical settings is mitapivat (AG-348), a PKM2 and PKLR activator being investigated for the treatment of several hematological disorders resulting from mutant forms of PK that exhibit lower catalytic activity than their wild-type counterparts (Kung et al., 2017). This drug has demonstrated a reasonable level of efficacy by increasing basal hemoglobin levels when administered to patients with PK deficiencies. However, despite these promising results, the high-dose regimen and twice-daily (BID) dosing frequency required to achieve efficacy highlight the need to develop more effective compounds with more favorable pharmacokinetic and improved safety profiles (Grace et al., 2019). The structure of mitapivat is: [ka] .

[0010] WO2020 / 167976A1 (Agios Pharmaceuticals) describes compounds that are said to modulate PK activity for the treatment of cancer, obesity, and diabetes-related disorders.

[0011] WO2023 / 052783, WO2023 / 079294, and WO2023 / 118875 (Sitryx Therapeutics Limited) disclose compounds that are PK modulators.

[0012] There remains a need to identify and develop novel disease-modifying PK modulators to fulfill several unmet medical needs associated with impaired PK function, particularly to develop compounds that exhibit favorable activity while also possessing advantageous physicochemical parameters. The compounds described herein as PK modulators, particularly PKM2 and / or PKLR modulators, and particularly PKM2 and / or PKLR activators, address these unmet needs by exhibiting favorable affinity and functional activity for PK enzymes, particularly PKM2 and / or PKLR, improved cellular pyruvate kinase activity compared to mitapivat, while possessing better overall physical / chemical properties with improved ADME and PK profiles, making them suitable for the treatment of human diseases associated with altered function of pyruvate kinase enzyme expression and / or activity. Summary of the Invention

[0013] (Summary of the Invention) The present invention provides compounds of formula (Ia): [ka] (In the formula: (a)R A is pyrazolyl and R B is pyridinyl substituted with one OMe group, and 6-((1H-pyrazol-4-yl)sulfonyl)-2-((5-methoxypyridin-2-yl)methyl)phthalazin-1(2H)-one [ka] Will it result in; (b)R A is pyrazolyl substituted by CHF2, and R B is pyrazolyl and 2-((1H-pyrazol-3-yl)methyl)-6-((1-(difluoromethyl)-1H-pyrazol-4-yl)sulfonyl)phthalazin-1(2H)-one [ka] Will it result in; (c)R A is pyrazolyl substituted by CH2CH2OH, and R B is dihydrofuro[3,2-b]pyridinyl, 2-((2,3-dihydrofuro[3,2-b]pyridin-5-yl)methyl)-6-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)sulfonyl)phthalazin-1(2H)-one [ka] Will it result in; (d)R A is pyrazolyl and R B is 2,3-dihydropyrazolo[5,1-b]oxazolyl and 6-((1H-pyrazol-4-yl)sulfonyl)-2-((2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)methyl)phthalazin-1(2H)-one [ka] Will it result in; (e)R A is pyrazolyl substituted by methyl, and R B is 2,3-dihydropyrazolo[5,1-b]oxazolyl, 2-((2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)methyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)phthalazin-1(2H)-one [ka] or (f)R A is pyrazolyl and R B is a pyrazolyl substituted with one Cl and one methyl, and is 6-((1H-pyrazol-3-yl)sulfonyl)-2-((4-chloro-5-methyl-1H-pyrazol-3-yl)methyl)phthalazin-1(2H)-one [ka] (resulting in or a salt and / or solvate thereof. DETAILED DESCRIPTION OF THE INVENTION

[0014] (Detailed Description of the Invention) In one embodiment, 6-((1H-pyrazol-4-yl)sulfonyl)-2-((5-methoxypyridin-2-yl)methyl)phthalazin-1(2H)-one [ka] or a salt and / or solvate thereof is provided.

[0015] In another embodiment, 6-((1H-pyrazol-4-yl)sulfonyl)-2-((5-methoxypyridin-2-yl)methyl)phthalazin-1(2H)-one [ka] is provided.

[0016] In another embodiment, 6-((1H-pyrazol-4-yl)sulfonyl)-2-((5-methoxypyridin-2-yl)methyl)phthalazin-1(2H)-one [ka] Salts, for example pharmaceutically acceptable salts, of the formula:

[0017] In one embodiment, 2-((1H-pyrazol-3-yl)methyl)-6-((1-(difluoromethyl)-1H-pyrazol-4-yl)sulfonyl)phthalazin-1(2H)-one [ka] or a salt and / or solvate thereof is provided.

[0018] In another embodiment, 2-((1H-pyrazol-3-yl)methyl)-6-((1-(difluoromethyl)-1H-pyrazol-4-yl)sulfonyl)phthalazin-1(2H)-one [ka] is provided.

[0019] In another embodiment, 2-((1H-pyrazol-3-yl)methyl)-6-((1-(difluoromethyl)-1H-pyrazol-4-yl)sulfonyl)phthalazin-1(2H)-one [ka] Salts, for example pharmaceutically acceptable salts, of the formula:

[0020] In one embodiment, 2-((2,3-dihydrofuro[3,2-b]pyridin-5-yl)methyl)-6-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)sulfonyl)phthalazin-1(2H)-one [ka] or a salt and / or solvate thereof is provided.

[0021] In another embodiment, 2-((2,3-dihydrofuro[3,2-b]pyridin-5-yl)methyl)-6-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)sulfonyl)phthalazin-1(2H)-one [ka] is provided.

[0022] In another embodiment, 2-((2,3-dihydrofuro[3,2-b]pyridin-5-yl)methyl)-6-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)sulfonyl)phthalazin-1(2H)-one [ka] Salts, for example pharmaceutically acceptable salts, of the formula:

[0023] In one embodiment, 6-((1H-pyrazol-4-yl)sulfonyl)-2-((2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)methyl)phthalazin-1(2H)-one [ka] or a salt and / or solvate thereof is provided.

[0024] In another embodiment, 6-((1H-pyrazol-4-yl)sulfonyl)-2-((2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)methyl)phthalazin-1(2H)-one [ka] is provided.

[0025] In another embodiment, 6-((1H-pyrazol-4-yl)sulfonyl)-2-((2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)methyl)phthalazin-1(2H)-one [ka] Salts, for example pharmaceutically acceptable salts, of the formula:

[0026] In one embodiment, 2-((2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)methyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)phthalazin-1(2H)-one [ka] or a salt and / or solvate thereof is provided.

[0027] In another embodiment, 2-((2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)methyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)phthalazin-1(2H)-one [ka] is provided.

[0028] In another embodiment, 2-((2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)methyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)phthalazin-1(2H)-one [ka] Salts, for example pharmaceutically acceptable salts, of the formula:

[0029] In one embodiment, 6-((1H-pyrazol-3-yl)sulfonyl)-2-((4-chloro-5-methyl-1H-pyrazol-3-yl)methyl)phthalazin-1(2H)-one [ka] or a salt and / or solvate thereof is provided.

[0030] In another embodiment, 6-((1H-pyrazol-3-yl)sulfonyl)-2-((4-chloro-5-methyl-1H-pyrazol-3-yl)methyl)phthalazin-1(2H)-one [ka] is provided.

[0031] In another embodiment, 6-((1H-pyrazol-3-yl)sulfonyl)-2-((4-chloro-5-methyl-1H-pyrazol-3-yl)methyl)phthalazin-1(2H)-one [ka] Salts, for example pharmaceutically acceptable salts, of the formula:

[0032] Therefore, the present invention provides 6-((1H-pyrazol-4-yl)sulfonyl)-2-((5-methoxypyridin-2-yl)methyl)phthalazin-1(2H)-one; 2-((1H-pyrazol-3-yl)methyl)-6-((1-(difluoromethyl)-1H-pyrazol-4-yl)sulfonyl)phthalazin-1(2H)-one; 2-((2,3-dihydrofuro[3,2-b]pyridin-5-yl)methyl)-6-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)sulfonyl)phthalazin-1(2H)-one; 6-((1H-pyrazol-4-yl)sulfonyl)-2-((2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)methyl)phthalazin-1(2H)-one; 2-((2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)methyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)phthalazin-1(2H)-one; 6-((1H-pyrazol-3-yl)sulfonyl)-2-((4-chloro-5-methyl-1H-pyrazol-3-yl)methyl)phthalazin-1(2H)-one; The present invention provides a compound selected from the group consisting of: or a salt and / or solvate thereof.

[0033] Compounds of formula (Ia) can be prepared as described in the Examples section below.

[0034] The present invention provides 2-((5-methoxypyridin-2-yl)methyl)-6-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)thio)phthalazin-1(2H)-one; 6-((1-(difluoromethyl)-1H-pyrazol-4-yl)thio)-2-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methyl)phthalazin-1(2H)-one; 6-((1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazol-4-yl)thio)-2-((2,3-dihydrofuro[3,2-b]pyridin-5-yl)methyl)phthalazin-1(2H)-one; 2-((2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)methyl)-6-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)thio)phthalazin-1(2H)-one; 2-((2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)methyl)-6-((1-methyl-1H-pyrazol-4-yl)thio)phthalazin-1(2H)-one; and 2-((4-chloro-5-methyl-1H-pyrazol-3-yl)methyl)-6-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)sulfonyl)phthalazin-1(2H)-one; The present invention provides a compound selected from the group consisting of: or a salt and / or solvate thereof.

[0035] The present invention relates to a process for the preparation of a compound of formula (Ia), comprising the step of: [ka] or a salt and / or solvate thereof; Oxidizing with an oxidizing agent such as oxone Includes; where R A and R B is defined elsewhere herein.

[0036] Suitably, the compound of formula (IIa) is [ka] or a salt and / or solvate thereof.

[0037] It will be understood that for use in therapy, salts of compounds of Formula (Ia) should be pharmaceutically acceptable. Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art. Pharmaceutically acceptable salts include acid addition salts, preferably salts of compounds of the present invention containing a basic group, such as an amino group, formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, or phosphoric acid. Also included are salts formed with organic acids, such as succinic acid, maleic acid, acetic acid, fumaric acid, citric acid, tartaric acid, benzoic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, and 1,5-naphthalenedisulfonic acid. Other salts, such as oxalates or formates, may be used, for example, in isolating compounds of Formula (Ia), and are also within the scope of the present invention, as are basic addition salts such as sodium, potassium, calcium, aluminum, zinc, magnesium, and other metal salts.

[0038] Pharmaceutically acceptable salts may be formed with organic bases such as basic amines, for example, ammonia, meglumine, tromethamine, piperazine, arginine, choline, diethylamine, benzathine, or lysine.Therefore, in one embodiment, the compound of formula (Ia) is provided in the form of a pharmaceutically acceptable salt.Alternatively, the compound of formula (Ia) is provided in the form of a free acid.When a compound contains a basic group and a free acid, it may be zwitterionic.

[0039] Suitably the compound of formula (Ia) is not a salt, for example not a pharmaceutically acceptable salt.

[0040] Suitably, the compound of formula (Ia) or the salt and / or solvate thereof is a pharmaceutically acceptable salt of the compound of formula (Ia).

[0041] Alternatively, the compound of formula (Ia) or a salt and / or solvate thereof is a compound of formula (Ia).

[0042] Suitably, when the compound of formula (Ia) is in the form of a salt, the pharmaceutically acceptable salt will be an acid addition salt such as an ammonium salt (formed, for example, with an inorganic acid such as HCl).

[0043] The compounds of formula (Ia) may be prepared in crystalline or non-crystalline form and, if crystalline, may optionally be solvated, for example as a hydrate. The present invention includes within its scope stoichiometric solvates (e.g., hydrates) and compounds containing variable amounts of solvent (e.g., water). Suitably, the compounds of formula (Ia) are not solvates.

[0044] The present invention extends to pharmaceutically acceptable derivatives of compounds of formula (Ia), such as pharmaceutically acceptable prodrugs thereof. Exemplary prodrugs of compounds of formula (Ia) that contain a carboxylic acid include esters thereof (e.g., C 1-6 Alkyl, e.g., C 1-4 and alkyl ester) derivatives. Thus, in one embodiment, the compound of formula (Ia) is provided as a pharmaceutically acceptable prodrug. In another embodiment, the compound of formula (Ia) is not provided as a pharmaceutically acceptable prodrug.

[0045] It should be understood that the present invention encompasses all isomers of the compounds of formula (Ia), including all geometric, tautomeric, and optical forms, as well as mixtures thereof (e.g., racemic mixtures). In particular, the present invention extends to all tautomeric forms of the compounds of formula (Ia). When additional chiral centers are present in the compounds of formula (Ia), the present invention includes within its scope all possible diastereoisomers, including mixtures thereof. The different isomeric forms can be separated or resolved one from the other by conventional methods, or any given isomer can be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses.

[0046] The present invention also includes all isotopic forms of the compounds provided herein, whether (i) in a form in which all atoms of a given atomic number have a mass number (or mixture of mass numbers) that is predominant in nature (referred to herein as a "natural isotopic form"), or (ii) in a form in which one or more atoms have the same atomic number but are replaced by an atom having a mass number different from the mass number of the atom that is predominant in nature (referred to herein as a "non-natural variant isotopic form"). It is understood that atoms may naturally exist as a mixture of mass numbers. The term "non-natural variant isotopic form" also includes embodiments in which the proportion of atoms of a given atomic number that have mass numbers less commonly found in nature (referred to herein as "uncommon isotopes") is increased relative to that occurring in nature, for example, to a level of >20%, >50%, >75%, >90%, >95%, or >99% of the number of atoms of that atomic number (the latter embodiment being referred to as an "isotopically enriched variant form"). The term "non-natural variant isotopic form" also includes embodiments in which the proportion of an uncommon isotope is reduced compared to that occurring in nature. Isotopic forms can include radioactive forms (i.e., which incorporate a radioactive isotope) and non-radioactive forms. Radioactive forms are typically isotopically enriched variant forms.

[0047] Therefore, non-natural variant isotopic forms of the compounds may be deuterium ( 2 H or D), carbon-11 ( 11 C), carbon-13( 13 C), carbon-14( 14 C), nitrogen-13( 13 N), nitrogen-15( 15 N), oxygen-15( 15 O), oxygen-17( 17 O), oxygen-18( 18 O), phosphorus-32( 32 P), sulfur-35( 35 S), chlorine-36( 36 Cl), chlorine-37( 37 Cl), fluorine-18( 18 F), iodine-123( 123 I), iodine-125( 125It may contain one or more artificial or unusual isotopes, such as I), in one or more atoms, or may contain an increased proportion of such isotopes in one or more atoms compared to the proportion that predominates in nature.

[0048] Non-natural variant isotopic forms containing radioactive isotopes can be used, for example, in drug and / or substrate tissue distribution studies. The radioactive isotope tritium, i.e. 3 H and carbon-14, i.e., 14 C is particularly useful for this purpose given its ease of incorporation and ready means of detection. 2 Non-natural variant isotopic forms incorporating H or D may offer certain therapeutic advantages due to greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in certain circumstances. 11 C. 18 F, 15 O, and 13 Non-natural variant isotopic forms can be prepared that incorporate positron emitting isotopes, such as N, and are useful in positron emission topography (PET) studies to examine substrate receptor occupancy.

[0049] In one embodiment, the compound of Formula (Ia) is provided in a natural isotopic form. In one embodiment, the compound of Formula (Ia) is provided in a non-natural variant isotopic form. In a specific embodiment, the non-natural variant isotopic form is provided in which deuterium (i.e., 2 In one embodiment, the atoms of the compound of formula (Ia) are in a non-radioactive isotopic form. In one embodiment, one or more atoms of the compound of formula (Ia) are in a radioactive isotopic form. Preferably, the radioisotope is a stable isotope. Preferably, the non-natural variant isotopic form is a pharmaceutically acceptable form.

[0050] In one embodiment, compounds of formula (Ia) are provided wherein a single atom of the compound exists in a non-natural variant isotopic form. In another embodiment, compounds of formula (Ia) are provided wherein two or more atoms exist in a non-natural variant isotopic form.

[0051] Non-natural isotopically variant forms can generally be prepared by conventional techniques known to those skilled in the art or by methods described herein, for example, methods similar to those described in the accompanying examples for preparing natural isotopically variant forms. Thus, non-natural isotopically variant forms can be prepared by substituting appropriate isotopically variant (or labeled) reagents for the conventional reagents utilized in the examples. Because the compounds of formula (Ia) are intended for use in pharmaceutical compositions, it will be readily understood that they are each preferably provided in substantially pure form, e.g., at least 60% pure, more preferably at least 75% pure, and preferably at least 85%, particularly at least 98% pure (percentages are on a weight-to-weight basis). Impure preparations of the compounds can be used to prepare purer forms for use in pharmaceutical compositions.

[0052] (treatment indication) The compounds of formula (Ia) are particularly useful in therapies for treating or preventing inflammatory diseases, diseases associated with undesired immune responses, cancer, obesity, diabetic diseases, or blood disorders. As shown in Biological Example 1 below, the tested example compounds of formula (Ia) exhibited improved PKM2 modulating activity compared to mitapivat. As shown in Biological Example 2 below, the tested example compounds of formula (Ia) also exhibited improved PKLR modulating activity, again using mitapivat as a comparative standard. As shown in Biological Example 3 below, the tested example compounds of formula (Ia) also exhibited in vitro antiproliferative activity. Therefore, the compounds of formula (Ia) are considered suitable for the treatment of diseases associated with PK, particularly PKM2 and PKLR activity.

[0053] Thus, in a first aspect, the present invention provides a compound of formula (Ia) as defined herein, or a pharmaceutically acceptable salt and / or solvate thereof, for use as a medicament. Also provided is a pharmaceutical composition comprising a compound of formula (Ia) as defined herein, or a pharmaceutically acceptable salt and / or solvate thereof. Such a pharmaceutical composition comprises a compound of formula (Ia) and one or more pharmaceutically acceptable diluents or carriers. Suitably, the present invention provides a pharmaceutical composition as defined above for use as a medicament. The following alternatives to the use of a compound of formula (Ia) apply equally to a pharmaceutical composition as defined herein comprising a compound of formula (Ia) as defined herein, or a pharmaceutically acceptable salt and / or solvate thereof.

[0054] In a further aspect, the present invention provides a compound of formula (Ia) or a pharmaceutically acceptable salt and / or solvate thereof as defined herein for use in the treatment or prevention of a disease, disorder, or condition associated with the function of PK, particularly PKM2 and / or PKLR. In a further aspect, the present invention provides the use of a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof in the manufacture of a medicament for treating or preventing a disease, disorder, or condition associated with the function of PK, particularly PKM2 and / or PKLR. In a further aspect, the present invention provides a method for treating or preventing a disease, disorder, or condition associated with the function of PK, particularly PKM2 and / or PKLR, which method comprises administering a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof.

[0055] In a further aspect, the present invention provides a compound of formula (Ia) or a pharmaceutically acceptable salt and / or solvate thereof as defined herein for use in the treatment or prevention of symptoms associated with diseases, disorders or conditions associated with the function of PKs, particularly PKM2 and / or PKLR. In a further aspect, the present invention provides the use of a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof in the manufacture of a medicament for treating or preventing symptoms associated with diseases, disorders or conditions associated with the function of PKs, particularly PKM2 and / or PKLR. In a further aspect, the present invention provides a method for treating or preventing symptoms associated with diseases, disorders or conditions associated with the function of PKs, particularly PKM2 and / or PKLR, comprising administering a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof.

[0056] In one embodiment, a compound of Formula (Ia) is a modulator of PKM2. In another embodiment, a compound of Formula (Ia) is an activator of PKM2. In one embodiment, a compound of Formula (Ia) is a modulator of PKLR. In another embodiment, a compound of Formula (Ia) is an activator of PKLR. A compound is an "activator" of a PK (e.g., PKM2 and / or PKLR) if it increases the activity of the enzyme, which can be quantified, for example, by determining the concentration of ATP produced in a suitable assay (e.g., Biological Example 1 for PKM2 and Biological Example 2 for PKLR).

[0057] In a further aspect, the present invention provides a compound of formula (Ia) as defined herein, or a pharmaceutically acceptable salt and / or solvate thereof, for use in the treatment or prevention of an inflammatory disease, a disease associated with an unwanted immune response, cancer, obesity, a diabetic disease, or a blood disorder. In a further aspect, the present invention provides the use of a compound of formula (Ia) as defined herein, or a pharmaceutically acceptable salt and / or solvate thereof, in the manufacture of a medicament for treating or preventing an inflammatory disease, a disease associated with an unwanted immune response, cancer, obesity, a diabetic disease, or a blood disorder. In a further aspect, the present invention provides a method of treating or preventing an inflammatory disease, a disease associated with an unwanted immune response, cancer, obesity, a diabetic disease, or a blood disorder, which method comprises administering a compound of formula (Ia) as defined herein, or a pharmaceutically acceptable salt and / or solvate thereof.

[0058] In a further aspect, the present invention provides a compound of formula (Ia) as defined herein, or a pharmaceutically acceptable salt and / or solvate thereof, for use in the treatment or prevention of an inflammatory disease, a disease associated with an unwanted immune response, cancer, obesity, a diabetic disease, or a condition associated with a blood disorder. In a further aspect, the present invention provides the use of a compound of formula (Ia) as defined herein, or a pharmaceutically acceptable salt and / or solvate thereof, in the manufacture of a medicament for treating or preventing an inflammatory disease, a disease associated with an unwanted immune response, cancer, obesity, a diabetic disease, or a condition associated with a blood disorder. In a further aspect, the present invention provides a method for treating or preventing an inflammatory disease, a disease associated with an unwanted immune response, cancer, obesity, a diabetic disease, or a condition associated with a blood disorder, the method comprising administering a compound of formula (Ia) as defined herein, or a pharmaceutically acceptable salt and / or solvate thereof.

[0059] For all aspects of the present invention, preferably the compound is administered to a subject in need thereof, which is preferably a human subject.

[0060] In one embodiment, there is provided a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof for use in the treatment of inflammatory diseases, diseases associated with an undesired immune response, cancer, obesity, diabetic diseases, or blood disorders. In one embodiment of the present invention, there is provided the use of a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof in the manufacture of a medicament for treating inflammatory diseases, diseases associated with an undesired immune response, cancer, obesity, diabetic diseases, or blood disorders. In one embodiment of the present invention, there is provided a method of treating inflammatory diseases, diseases associated with an undesired immune response, cancer, obesity, diabetic diseases, or blood disorders, comprising administering a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof.

[0061] In one embodiment, there is provided a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof for use in the treatment of inflammatory diseases, diseases associated with an undesired immune response, cancer, obesity, diabetic diseases, or conditions associated with blood disorders. In one embodiment of the present invention, there is provided the use of a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof in the manufacture of a medicament for treating inflammatory diseases, diseases associated with an undesired immune response, cancer, obesity, diabetic diseases, or conditions associated with blood disorders. In one embodiment of the present invention, there is provided a method of treating inflammatory diseases, diseases associated with an undesired immune response, cancer, obesity, diabetic diseases, or conditions associated with blood disorders, comprising administering a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof.

[0062] In one embodiment, there is provided a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof for use in the prevention of inflammatory diseases, diseases associated with an undesired immune response, cancer, obesity, diabetic diseases, or blood disorders. In one embodiment of the present invention, there is provided the use of a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof in the manufacture of a medicament for preventing inflammatory diseases, diseases associated with an undesired immune response, cancer, obesity, diabetic diseases, or blood disorders. In one embodiment of the present invention, there is provided a method for preventing inflammatory diseases, diseases associated with an undesired immune response, cancer, obesity, diabetic diseases, or blood disorders, comprising administering a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof.

[0063] In one embodiment, there is provided a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof for use in the prevention of inflammatory diseases, diseases associated with an undesired immune response, cancer, obesity, diabetic diseases, or symptoms associated with a blood disorder. In one embodiment of the present invention, there is provided the use of a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof in the manufacture of a medicament for preventing inflammatory diseases, diseases associated with an undesired immune response, cancer, obesity, diabetic diseases, or symptoms associated with a blood disorder. In one embodiment of the present invention, there is provided a method for preventing inflammatory diseases, diseases associated with an undesired immune response, cancer, obesity, diabetic diseases, or symptoms associated with a blood disorder, comprising administering a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof.

[0064] In one embodiment, there is provided a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof for use in the treatment or prevention of inflammatory diseases. In one embodiment of the invention, there is provided the use of a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof in the manufacture of a medicament for treating or preventing inflammatory diseases. In one embodiment of the invention, there is provided a method of treating or preventing inflammatory diseases, the method comprising administering a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof.

[0065] In one embodiment, there is provided a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof for use in the treatment or prevention of symptoms associated with inflammatory diseases. In one embodiment of the invention, there is provided the use of a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof in the manufacture of a medicament for treating or preventing symptoms associated with inflammatory diseases. In one embodiment of the invention, there is provided a method of treating or preventing symptoms associated with inflammatory diseases, comprising administering a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof.

[0066] In one embodiment, there is provided a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof for use in treating or preventing inflammation associated with an inflammatory disease. In one embodiment of the invention, there is provided the use of a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof in the manufacture of a medicament for treating or preventing inflammation associated with an inflammatory disease. In one embodiment of the invention, there is provided a method of treating or preventing inflammation associated with an inflammatory disease, comprising administering a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof.

[0067] In one embodiment, there is provided a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof for use in the treatment or prevention of a disease associated with an unwanted immune response. In one embodiment of the invention, there is provided the use of a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof in the manufacture of a medicament for treating or preventing a disease associated with an unwanted immune response. In one embodiment of the invention, there is provided a method of treating or preventing a disease associated with an unwanted immune response, which method comprises administering a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof.

[0068] In one embodiment, there is provided a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof for use in the treatment or prevention of symptoms associated with diseases associated with an undesired immune response. In one embodiment of the invention, there is provided the use of a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof in the manufacture of a medicament for treating or preventing symptoms associated with diseases associated with an undesired immune response. In one embodiment of the invention, there is provided a method of treating or preventing symptoms associated with diseases associated with an undesired immune response, the method comprising administering a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof.

[0069] In one embodiment, there is provided a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof for use in the treatment or prevention of inflammation associated with a disease associated with an undesired immune response. In one embodiment of the invention, there is provided the use of a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof in the manufacture of a medicament for treating or preventing inflammation associated with a disease associated with an undesired immune response. In one embodiment of the invention, there is provided a method of treating or preventing inflammation associated with a disease associated with an undesired immune response, comprising administering a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof.

[0070] In one embodiment, there is provided a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof for use in the treatment or prevention of cancer. In one embodiment of the invention, there is provided the use of a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof in the manufacture of a medicament for treating or preventing cancer. In one embodiment of the invention, there is provided a method of treating or preventing cancer, which method comprises administering a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof.

[0071] In one embodiment, there is provided a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof for use in the treatment or prevention of a condition associated with cancer. In one embodiment of the invention, there is provided the use of a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof in the manufacture of a medicament for treating or preventing a condition associated with cancer. In one embodiment of the invention, there is provided a method of treating or preventing a condition associated with cancer, which method comprises administering a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof.

[0072] In one embodiment, there is provided a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof for use in the treatment or prevention of obesity. In one embodiment of the invention, there is provided the use of a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof in the manufacture of a medicament for treating or preventing obesity. In one embodiment of the invention, there is provided a method of treating or preventing obesity, which method comprises administering a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof.

[0073] In one embodiment, there is provided a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof for use in the treatment or prevention of symptoms associated with obesity. In one embodiment of the invention, there is provided the use of a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof in the manufacture of a medicament for treating or preventing symptoms associated with obesity. In one embodiment of the invention, there is provided a method of treating or preventing symptoms associated with obesity, which method comprises administering a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof.

[0074] In one embodiment, there is provided a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof for use in the treatment or prevention of diabetic disease. In one embodiment of the invention, there is provided the use of a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof in the manufacture of a medicament for treating or preventing diabetic disease. In one embodiment of the invention, there is provided a method of treating or preventing diabetic disease, the method comprising administering a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof.

[0075] In one embodiment, there is provided a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof for use in the treatment or prevention of symptoms associated with diabetic disease. In one embodiment of the invention, there is provided the use of a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof in the manufacture of a medicament for treating or preventing symptoms associated with diabetic disease. In one embodiment of the invention, there is provided a method of treating or preventing symptoms associated with diabetic disease, the method comprising administering a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof.

[0076] In one embodiment, there is provided a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof for use in the treatment or prevention of a blood disorder. In one embodiment of the invention, there is provided the use of a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof in the manufacture of a medicament for treating or preventing a blood disorder. In one embodiment of the invention, there is provided a method of treating or preventing a blood disorder, which method comprises administering a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof.

[0077] In one embodiment, there is provided a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof for use in the treatment or prevention of a condition associated with a blood disorder. In one embodiment of the invention, there is provided the use of a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof in the manufacture of a medicament for treating or preventing a condition associated with a blood disorder. In one embodiment of the invention, there is provided a method of treating or preventing a condition associated with a blood disorder, which method comprises administering a compound of formula (Ia) as defined herein or a pharmaceutically acceptable salt and / or solvate thereof.

[0078] An unwanted immune response is typically an immune response that results in a pathological condition, ie, a pathological immune response or reaction.

[0079] In one embodiment, the inflammatory disease or disease associated with an unwanted immune response is an autoimmune disease.

[0080] In one embodiment, the inflammatory disease or disease associated with an unwanted immune response is psoriasis (including chronic plaque psoriasis, erythrodermic psoriasis, pustular psoriasis, guttate psoriasis, inverse psoriasis, and nail variant psoriasis), asthma, chronic obstructive pulmonary disease (including COPD, chronic bronchitis, and emphysema), heart failure (including left ventricular failure), myocardial infarction, angina pectoris, other atherosclerosis and / or atherothrombosis related disorders (including peripheral vascular disease and ischemic stroke), mitochondrial and neurodegenerative diseases (e.g., Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, retinal fibrosis ... pigmentary degeneration, or mitochondrial encephalomyopathy), autoimmune paraneoplastic retinopathy, transplant rejection (including antibody-mediated and T-cell mediated forms), multiple sclerosis, transverse myelitis, ischemia-reperfusion injury (e.g., during elective surgery such as cardiopulmonary bypass for coronary artery bypass grafting or other cardiac surgery, after percutaneous coronary intervention, treatment of acute ST-segment elevation myocardial infarction or ischemic stroke, organ transplant, or after acute compartment syndrome), AGE-induced genomic damage, inflammatory bowel disease (e.g., Crohn's disease or ulcerative colitis), primary sclerosing cholangitis (PSCs), SC), PSC-autoimmune hepatitis overlap syndrome, non-alcoholic fatty liver disease (non-alcoholic steatohepatitis), rheumatica, granuloma annulare, cutaneous lupus erythematosus (CLE), systemic lupus erythematosus (SLE), lupus nephritis, drug-induced lupus, autoimmune myocarditis or myopericarditis, Dressler syndrome, giant cell myocarditis, post-pericardiotomy syndrome, drug-induced hypersensitivity syndrome (including hypersensitivity myocarditis), eczema, sarcoidosis, erythema nodosum, acute disseminated encephalomyelitis (ADEM), neuromyelitis optica spectrum disorder, MOG (myelination syndrome). phosphooligodendrocyte glycoprotein (MOG-EM) antibody-related disorders (including MOG-EM), optic neuritis, CLIPPERS (chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids), diffuse myelin-destructive sclerosis, Addison's disease, alopecia areata, ankylosing spondylitis, other spondyloarthritis (including peripheral spondyloarthritis associated with psoriasis, inflammatory bowel disease, reactive arthritis, or juvenile-onset forms), antiphospholipid syndrome, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease, pemphigoid (bullous pemphigoid, mucous membrane pemphigoid, cicatricial pemphigoid, herpes gestationis or pemphigoid of gestationis),Ocular cicatricial pemphigoid), linear IgA disease, Behçet's disease, celiac disease, Chagas' disease, dermatomyositis, type 1 diabetes, endometriosis, Goodpasture's syndrome, Graves' disease, Guillain-Barré syndrome and its subtypes (acute inflammatory demyelinating polyneuropathy, AIDP, acute motor axonal neuropathy (AMAN), acute motor and sensory axonal neuropathy (AMSAN), pharyngo-cervical-brachial type, Miller-Fisher syndrome, type, and Bickerstaff brainstem encephalitis), progressive inflammatory neuropathy, Hashimoto's disease, hidradenitis suppurativa, inclusion body myositis, necrotizing myopathy, Kawasaki disease, IgA nephropathy, Henoch-Schönlein purpura, idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura (TTP), Evans syndrome, interstitial cystitis, mixed connective tissue disease, undifferentiated connective tissue disease, morphea, myasthenia gravis (including MuSK antibody positive and seronegative types), narcolepsy C, neuromyotonia, pemphigus vulgaris, pernicious anemia, psoriatic arthritis, polymyositis, primary biliary cholangitis (also known as primary biliary cirrhosis), rheumatoid arthritis, relapsing rheumatoid arthritis, schizophrenia, autoimmune (meningo)encephalitis syndrome, scleroderma (including focal and diffuse), Sjögren's syndrome, stiff-person syndrome, polymyalgia rheumatica, giant cell arteritis (temporal arteritis), Takayasu's arteritis, polyarteritis nodosa, Kawasaki disease, and rheumatoid arthritis with polyangiitis Granulomatosis (GPA; formerly Wegener's granulomatosis), eosinophilic granulomatosis with polyangiitis (EGPA; formerly Churg-Strauss syndrome), microscopic polyarteritis / polyangiitis, hypocomplementemic urticarial vasculitis, hypersensitivity vasculitis, cryoglobulinemia, thromboangiitis obliterans (Buerger's disease), vasculitis, leukocytoclastic vasculitis, vitiligo, acute disseminated encephalomyelitis, adrenoleukodystrophy, Alexander disease, Alper's disease disease), Barrow concentric sclerosis or Marburg disease, idiopathic organizing pneumonia (formerly known as bronchiolitis obliterans organizing pneumonia), Canavan disease, central nervous system vasculitis syndrome, Charcot-Marie-Tooth disease, childhood ataxia with central nervous system hypomyelination, chronic inflammatory demyelinating polyneuropathy (CIDP), diabetic retinopathy, globoid cell leukodystrophy (Krabbe disease), graft-versus-host disease (GVHD) (including acute and chronic forms, and intestinal GVHD), hepatitis C (HCV) infection or complications, herpes simplex virus infection or complications,Human immunodeficiency virus (HIV) infection or complications, lichen planus, monolimbic muscular atrophy, fibrosis, cystic fibrosis, pulmonary arterial hypertension (PAH, including idiopathic PAH), pulmonary sarcoidosis, idiopathic pulmonary fibrosis, renal fibrosis, hepatic fibrosis, pulmonary fibrosis, childhood asthma, atopic dermatitis, allergic dermatitis, contact dermatitis, allergic rhinitis, rhinitis, sinusitis, conjunctivitis, allergic conjunctivitis, keratoconjunctivitis sicca, dry eye, xerophthalmia, glaucoma, macular edema, diabetic macular edema, central retinal vein occlusion (CRVO), macular degeneration (dry and / or wet age-related macular degeneration, AM) D), postoperative cataract inflammation, uveitis (including posterior, anterior, intermediate, and panuveitis), iridocyclitis, scleritis, corneal transplant and limbal cell transplant rejection, gluten-sensitive enteropathy (celiac disease), dermatitis herpetiformis, eosinophilic esophagitis, achalasia, autoimmune autonomic neuropathy, autoimmune encephalomyelitis, autoimmune oophoritis, autoimmune orchitis, autoimmune pancreatitis, aortitis and periaortitis, autoimmune retinopathy, autoimmune urticaria, Behçet's disease, (idiopathic) Castleman's disease, Cogan's syndrome, IgG4-related disease, retroperitoneal fibrosis, systemic juvenile idiopathic arthritis Juvenile idiopathic arthritis, including Still's disease, adult-onset Still's disease, lignified conjunctivitis, Mooren's ulcer, acute pityriasis lichenoides (PLEVA, also known as Much-Habermann disease), multifocal motor neuropathy (MMN), childhood acute-onset neuropsychiatric syndromes (PANS), including pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS), paraneoplastic syndromes, including paraneoplastic cerebellar degeneration, Lambert-Eaton myasthenic syndrome, limbic encephalitis, brainstem encephalitis, opsoclonus-myoclonus ataxia syndrome, anti-NMDA receptor encephalitis, and thymoma-associated multisystem autoimmunity. (including perivenous encephalomyelitis, reflex sympathetic dystrophy, relapsing polychondritis, sperm and testicular autoimmunity, Susac syndrome, Tolosa-Hunt syndrome, Vogt-Koyanagi-Harada disease, antisynthetase syndrome, autoimmune enteropathy, X-linked immunodysregulation-polyendocrinopathy-enteropathy (IPEX), microscopic colitis, autoimmune lymphoproliferative syndrome (ALPS), autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APEX), gout, pseudogout, amyloid (including AA or secondary amyloidosis), eosinophilic fasciitis (Schulman syndrome),Progesterone hypersensitivity (including progesterone dermatitis), familial Mediterranean fever (FMF), tumor necrosis factor (TNF) receptor-associated periodic fever syndrome (TRAPS), hyperglobulin Demia with periodic fever syndrome (HIDS), PAPA (septic arthritis, pyoderma gangrenosum, severe cystic acne) syndrome, interleukin-1 receptor antagonist deficiency (DIRA), interleukin-36 receptor antagonist deficiency (DITRA), cryopyrin-associated periodic syndrome (CAP) S) (including familial cold autoinflammatory syndrome [FCAS], Muckle-Wells syndrome, and neonatal-onset multisystem inflammatory disease [NOMID]), NLRP12-associated autoinflammatory disorder (NLRP12AD), periodic febrile aphthous stomatitis (PFAPA), chronic atypical neutrophilic dermatosis with lipoatrophy and elevated body temperature (CANDLE), Majeed syndrome, Blau syndrome (also known as juvenile systemic granulomatosis), macrophage activation syndrome, chronic relapsing multifocal osteomyelitis (CRMO), familial cold autoinflammatory disorder (FAC12AD), and Autoinflammatory syndromes, mutant adenosine deaminase 2 and monogenic interferonopathies (including Aicardi-Goutieres syndrome, retinal vasculopathy with cerebral leukodystrophy, spinal intrachondrodysplasia, infantile-onset STING [stimulator of interferon genes]-associated vasculopathy, proteasome-associated autoinflammatory syndrome, familial chilblain-like lupus, hereditary symmetrical pigmentary dysplasia), Schnitzler syndrome; familial cylindromatosis, congenital B-cell lymphocytosis, OTULIN-related The present invention relates to or is associated with a disease selected from the group consisting of: diabetes mellitus, type 2 diabetes, insulin resistance and metabolic syndrome (including obesity-related inflammation), atherosclerotic disorders (e.g., myocardial infarction, angina pectoris, ischemic heart failure, ischemic nephropathy, ischemic stroke, peripheral vascular disease, aortic aneurysm), renal inflammatory disorders (e.g., diabetic nephropathy, membranous nephropathy, minimal change disease, crescentic glomerulonephritis, acute kidney injury, renal transplant), wound healing, keloid formation, and prurigo nodularis.

[0081] In one embodiment, the inflammatory disease or disease associated with an unwanted immune response is selected from the following autoinflammatory diseases: familial Mediterranean fever (FMF), tumor necrosis factor (TNF) receptor-associated periodic fever syndrome (TRAPS), hyperglobulin Demia with periodic fever syndrome (HIDS), PAPA (septic arthritis, pyoderma gangrenosum, and severe cystic acne) syndrome, interleukin-1 receptor antagonist deficiency (DIRA), interleukin-36-receptor antagonist deficiency (DITRA), cryopyrin-associated periodic syndromes (CAPS) (including familial cold autoinflammatory syndrome [FCAS], Muckle-Wells syndrome, and neonatal-onset multisystem inflammatory disease [NOMID]), NLRP12-associated autoinflammatory disorder (NLRP12AD), periodic being or associated with a disorder selected from fever-related aphthous stomatitis (PFAPA), chronic atypical neutrophilic dermatosis with lipoatrophy and elevated body temperature (CANDLE), Majeed syndrome, Blau syndrome (also known as juvenile systemic granulomatosis), macrophage activation syndrome, chronic relapsing multifocal osteomyelitis (CRMO), familial cold autoinflammatory syndrome, mutant adenosine deaminase 2 and monogenic interferonopathies (including Aicardi-Goutieres syndrome, retinal vasculopathy with cerebral leukodystrophy, spinal enchondrodysplasia, infantile-onset STING [stimulator of interferon genes]-associated vasculopathy, proteasome-associated autoinflammatory syndrome, familial chilblain-like lupus, hereditary symmetrical pigmentary dysplasia), and Schnitzler syndrome.

[0082] In one embodiment, the inflammatory disease or disease associated with an unwanted immune response is mediated by excessive NF-κB or gain of function in the NF-κB signaling pathway, or is a disease in which there is a significant contribution to the pathogenesis (including non-canonical NF-κB signaling) including the following: familial cylindromatosis, congenital B-cell lymphocytosis, OTULIN-associated autoinflammatory syndrome, type 2 diabetes, insulin resistance, and metabolic syndrome (obesity-related). The disease is or is associated with a disease selected from: inflammatory bowel disease (including inflammatory bowel disease), atherosclerotic disorders (e.g., myocardial infarction, angina pectoris, ischemic heart failure, ischemic nephropathy, ischemic stroke, peripheral vascular disease, aortic aneurysm), renal inflammatory disorders (e.g., diabetic nephropathy, membranous nephropathy, minimal change disease, crescentic glomerulonephritis, acute kidney injury, renal transplant), asthma, COPD, type 1 diabetes, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease (including ulcerative colitis and Crohn's disease), and SLE.

[0083] In one embodiment, the inflammatory disease or disease associated with an unwanted immune response is or is associated with a disease selected from the group consisting of Crohn's disease, ulcerative colitis, type 2 diabetes, atopic dermatitis, hidradenitis suppurativa, psoriasis, bullous pemphigoid, pemphigus vulgaris, localized and diffuse scleroderma, Sjogren's syndrome, polymyositis, dermatomyositis, Behcet's disease, wound healing, rheumatoid arthritis, systemic lupus erythematosus, cutaneous lupus erythematosus, graft versus host disease, multiple sclerosis, organ fibrosis (including liver, lung, kidney), COPD, and asthma.

[0084] In one embodiment, the inflammatory disease or disease associated with an unwanted immune response is or is associated with a disease selected from rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, systemic lupus erythematosus, multiple sclerosis, psoriasis, inflammatory bowel disease (including ulcerative colitis and Crohn's disease), atopic dermatitis, fibrosis, uveitis, cryopyrin-associated periodic syndrome, Muckle-Wells syndrome, juvenile idiopathic arthritis, chronic obstructive pulmonary disease, and asthma.

[0085] In one embodiment, the disease is multiple sclerosis.

[0086] In one embodiment, the disease is psoriasis.

[0087] In one embodiment, the disease is asthma.

[0088] In one embodiment, the disease is chronic obstructive pulmonary disease.

[0089] In one embodiment, the disease is systemic lupus erythematosus.

[0090] In one embodiment, the disease is rheumatoid arthritis.

[0091] In one embodiment, the disease is inflammatory bowel disease (including ulcerative colitis and Crohn's disease).

[0092] In one embodiment, the disease is atopic dermatitis.

[0093] In one embodiment, the disease is fibrosis.

[0094] In one embodiment, the cancer is acute lymphoblastic leukemia, adult; acute lymphoblastic leukemia, pediatric; acute myeloid leukemia, adult; adrenocortical carcinoma; adrenocortical carcinoma, pediatric; AIDS-related lymphoma; AIDS-related malignancies; anal cancer; astrocytoma, pediatric cerebellum; astrocytoma, pediatric cerebral; Barrett's esophagus (premalignant syndrome); cholangiocarcinoma, extrahepatic; bladder cancer; bladder cancer, pediatric; bone cancer, osteosarcoma / malignant fibrous histiocytoma; brain stem glioma, pediatric; brain tumor, adult; brain tumor, brain stem glioma, pediatric; brain tumor, cerebellar astrocytoma, pediatric; brain tumor, cerebral astrocytoma / malignant glioma, pediatric; brain tumor, ependymoma, pediatric; brain tumor, medulloblastoma, Pediatric;Brain Tumor, Supratentorial Primitive Neuroectodermal Tumor, Pediatric;Brain Tumor, Optic Pathway and Hypothalamic Glioma, Pediatric;Brain Tumor, Pediatric (Other);Breast Cancer;Breast Cancer and Pregnancy;Breast Cancer, Pediatric;Breast Cancer, Male;Bronchial Adenoma / Carcinoid, Pediatric;Carcinoid Tumor, Pediatric;Carcinoid Tumor, Gastrointestinal;Carcinoma, Adrenal Cortex;Carcinoma, Pancreatic Islet Cell;Carcinoma of Unknown Primary;Central Nervous System Lymphoma, Primary;Cerebellar Astrocytoma, Pediatric;Cerebral Astrocytoma / Malignant Glioma, Pediatric;Cervical Cancer;Pediatric Cancer;Chronic Lymphocytic Leukemia;Chronic Myelogenous Leukemia;Chronic Myeloproliferative Disorder;Clear Cell Sarcoma of the Tendon Sheath;Colon Cancer;Colorectal Cancer;Colorectal Cancer, Pediatric;Cutaneous T Cell lymphoma;Endometrial carcinoma;Ependymoma, pediatric;Epithelial carcinoma, ovarian;Esophageal cancer;Esophageal cancer, pediatric;Ewing family tumors;Extracranial germ cell tumors, pediatric;Extragonadal germ cell tumors;Extrahepatic bile duct carcinoma;Eye cancer, intraocular melanoma;Eye cancer, retinoblastoma;Gallbladder cancer;Gastric cancer;Gastric cancer, pediatric;Gastrointestinal carcinoid tumors;Germ cell tumors, extracranial, pediatric;Germ cell tumors, extragonadal;Germ cell tumors, ovarian;Gestational trophoblastic tumors;Glioma, pediatric brainstem;Glioma, pediatric visual pathway and hypothalamic;Hairy cell leukemia;Head and neck cancer;Hepatocellular (liver) carcinoma;Hepatocellular (liver) carcinoma, adult (primary);Hepatocellular (liver) carcinoma, pediatric (primary);Esophageal Cancer of the liver;Hodgkin's lymphoma;Hodgkin's lymphoma, adult;Hodgkin's lymphoma, childhood;Hodgkin's lymphoma, pregnancy;Hypopharyngeal cancer;Hypothalamic and optic tract glioma, childhood;Intraocular melanoma;Islet cell carcinoma (endocrine pancreas);Cancers of the endocrine system (e.g., cancer of the thyroid, pancreas, parathyroid, or adrenal gland);Kaposi's sarcoma;Kidney cancer;Laryngeal cancer;Laryngeal cancer, childhood;Leukemia, acute lymphoblastic, adult;Leukemia, acute lymphoblastic, childhood;Leukemia, acute myeloid, adult;Leukemia, acute myeloid, childhood;Leukemia, chronic lymphocytic;Leukemia, chronic myeloid;Leukemia, hairy cell;Lymphocytic lymphoma;Lip and oral cavity cancer;Liver cancer, adult (primary); Liver cancer, pediatric (primary); Lung cancer; Lung cancer, non-small cell; Lung cancer, small cell; Lymphoblastic leukemia, adult acute; Lymphoblastic leukemia, childhood acute; Lymphocytic leukemia, chronic; Lymphoma, AIDS-related; Lymphoma, central nervous system (primary); Lymphoma, cutaneous T-cell; Lymphoma, Hodgkin, adult; Lymphoma, Hodgkin, childhood; Lymphoma, Hodgkin, pregnancy; Lymphoma, non-Hodgkin, adult; Lymphoma, non-Hodgkin, childhood; Lymphoma, non-Hodgkin, pregnancy; Lymphoma, central nervous system primary; Waldenstrom macroglobulinemia; Male breast cancer; Malignant mesothelioma, adult; Malignant mesothelioma, pediatric; Malignant thymoma; Medulloblastoma, pediatric; Melanoma; Melanoma, intraocular; Merkel cell carcinoma; Mesothelioma, malignant; Metastatic squamous cell carcinoma of the neck with unknown primary; Multiple endocrine neoplasia syndrome, pediatric; Multiple myeloma / plasma cell neoplasm; Mycosis fungoides; Myelodysplastic syndrome; Myeloid leukemia, chronic; Myeloid leukemia, acute, pediatric; Myeloma, multiple; Myeloproliferative disorders, chronic; Cancer of the nasal cavity and paranasal sinuses; Nasopharyngeal carcinoma; Nasopharyngeal carcinoma, pediatric; Neoplastic skin diseases; Neuroblastoma; Non-Hodgkin's lymphoma, adult; Non-Hodgkin's lymphoma, pediatric; Non-Hodgkin's lymphoma during pregnancy; Non-small cell lung cancer; New carcinoma of the central nervous system Biological (e.g., primary CNS lymphoma, spinal axis tumor, medulloblastoma, brainstem glioma, or pituitary adenoma); oat cell carcinoma; oral cavity cancer, pediatric; oral cavity and lip cancer; oropharyngeal cancer; osteosarcoma / malignant fibrous histiocytoma of bone; ovarian cancer; ovarian cancer, pediatric; ovarian epithelial cancer; ovarian germ cell tumor; ovarian low malignant potential tumor; pediatric malignancies; pancreatic cancer; pancreatic cancer, pediatric; pancreatic islet cell cancer; paranasal and nasal sinus cancer; parathyroid cancer; penile cancer; pheochromocytoma; pineal and supratentorial primitive neuroectodermal tumor, pediatric; pituitary tumor; plasma cell neoplasm / multiple myeloma; pleuropulmonary blastoma; pregnancy and breast cancer; pregnancy and Hodgkin's lymphoma; pregnancy and non-Hodgkin's lymphoma Lymphoma; Primary central nervous system lymphoma; Primary liver cancer, adult; Primary liver cancer, pediatric; Prostate cancer (especially hormone-refractory); Chronic or acute leukemia; Pediatric solid tumors; Hypereosinophilia; Rectal cancer; Renal cell (kidney) cancer; Renal cell carcinoma, pediatric; Renal pelvis and ureter, transitional cell carcinoma; Retinoblastoma; Rhabdomyosarcoma, pediatric; Salivary gland cancer; Salivary gland cancer, pediatric; Sarcoma, Ewing's family of tumors; Sarcoma, Kaposi's; Sarcoma (osteosarcoma) / malignant fibrous histiocytoma of bone; Sarcoma, rhabdomyosarcoma, pediatric; Sarcoma of soft tissue; Sarcoma, soft tissue, adult; Sarcoma, soft tissue, pediatric; Sezary syndrome; Skin cancer; Skin cancer, pediatric;Skin cancer (melanoma); Skin cancer, Merkel cell; Small cell lung cancer; Dermatofibrosarcoma protuberans; Small intestine cancer; Soft tissue sarcoma, adult; Soft tissue sarcoma, pediatric; Head and neck cancer; Squamous cell neck carcinoma of unknown primary, metastatic; Gastric cancer; Gastric cancer, pediatric; Supratentorial primitive neuroectodermal tumor, pediatric; The tumor is selected from the group consisting of T-cell lymphoma, skin; testicular cancer; thymoma, pediatric; thymoma, malignant; thyroid cancer; thyroid cancer, pediatric; transitional cell carcinoma of the renal pelvis and ureter; trophoblastic tumor, gestational; pediatric cancer of unknown primary site; rare cancers of childhood; ureter and renal pelvis, transitional cell carcinoma; urethral cancer; ureteral cancer (e.g., renal cell carcinoma, renal pelvis cancer); penile cancer; gynecological tumors; uterine cancer; uterine sarcoma; fallopian tube cancer; endometrial cancer; vaginal cancer; vaginal cancer; vulvar cancer; visual tract and hypothalamic glioma, pediatric; vulvar cancer; Waldenstrom's macroglobulinemia; and Wilms' tumor.

[0095] In one embodiment, the cancer is selected from the group consisting of lung cancer; NSCLC (non-small cell lung cancer); oat cell carcinoma; bone cancer; pancreatic cancer; skin cancer; dermatofibrosarcoma protuberans; cancer of the head and neck; cutaneous or intraocular melanoma; uterine cancer; ovarian cancer; colorectal cancer; anal cancer; gastric cancer; colon cancer; breast cancer; gynecological tumors (e.g., uterine sarcoma, cancer of the fallopian tubes, cancer of the endometrium, cancer of the cervix, cancer of the vagina, or cancer of the vulva); Hodgkin's disease; hepatocellular carcinoma; cancer of the esophagus; small intestine cancer; cancer of the endocrine system (e.g., cancer of the thyroid, pancreas, parathyroid, or adrenal gland); soft tissue tumors. The cancer is selected from the group consisting of sarcoma of the urinary tract; urethral cancer; penile cancer; prostate cancer (especially hormone-refractory); chronic or acute leukemia; pediatric solid tumors; hypereosinophilia; lymphocytic lymphoma; bladder cancer; kidney cancer; ureteral cancer (e.g., renal cell carcinoma, renal pelvic cancer); pediatric malignancies; central nervous system neoplasms (e.g., primary CNS lymphoma, spinal axis tumor, medulloblastoma, brainstem glioma, or pituitary adenoma); Barrett's esophagus (premalignant syndrome), and neoplastic skin diseases.

[0096] "Obesity" refers to the condition in which a subject has a body mass index of 30 or greater. Body mass index (BMI) is in accordance with the "NIH Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults" (1998).

[0097] In one embodiment, administering a compound of Formula (Ia) to a subject reduces the subject's BMI to less than 30, for example, less than 29, less than 28, less than 27, less than 26, or less than 25. In one embodiment, a compound of Formula (Ia) is used to treat or prevent abnormal or inappropriate weight gain, metabolic rate, or fat deposition, for example, anorexia, hyperphagia, obesity, diabetes, or hyperlipidemia (e.g., elevated triglycerides and / or elevated cholesterol), and disorders of fat or lipid metabolism. In one embodiment, a compound of Formula (Ia) is used to treat or prevent metabolic syndrome.

[0098] In one embodiment, the compound of Formula (Ia) is used to treat obesity associated with Prader-Willi syndrome (PWS). In one embodiment, the compound of Formula (Ia) is used to reduce body fat, prevent body fat gain, reduce cholesterol (e.g., total cholesterol and / or the ratio of total cholesterol to HDL cholesterol), and / or reduce appetite, and / or reduce co-morbidities such as diabetes, cardiovascular disease, and stroke in individuals with PWS-associated obesity.

[0099] "Diabetic disease" means diabetes mellitus ("diabetes") or diabetic complications. The two main types of diabetes are (i) type 1 diabetes, which results from the pancreas not producing insulin and the usual treatment is insulin replacement therapy, and (ii) type 2 diabetes, in which patients either produce insufficient insulin or are insulin resistant. Diabetic complications include microvascular and macrovascular complications and include coronary artery disease, peripheral artery disease, stroke, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic kidney disease, and NASH.

[0100] In one embodiment, the "blood disorder" is selected from the group consisting of thalassemia (e.g., β-thalassemia), hereditary spherocytosis, hereditary elliptocytosis, abetalipoproteinemia (or Bassen-Kornzweig syndrome), paroxysmal nocturnal hemoglobinuria, acquired hemolytic anemia (e.g., congenital anemia (e.g., enzymopathy)), anemia of chronic disease, pyruvate kinase deficiency (PKD), and sickle cell disease.

[0101] (Administration) References in this section to compounds of formula (Ia) will be understood to include compounds of formula (Ia) or pharmaceutically acceptable salts and / or solvates thereof, preferably compounds of formula (Ia).

[0102] The compound of formula (Ia) is usually administered as a pharmaceutical composition. Thus, in one embodiment, there is provided a pharmaceutical composition comprising a compound of formula (Ia) and one or more pharmaceutically acceptable diluents or carriers.

[0103] The compounds of formula (Ia) may be administered by any convenient method, for example by oral, parenteral, buccal, sublingual, nasal, rectal, intrathecal or transdermal administration, and the pharmaceutical composition may be adapted accordingly.

[0104] The compounds of formula (Ia) can be administered locally to a target organ, for example, to the eye, lung, nose, or skin. Accordingly, the present invention provides pharmaceutical compositions comprising a compound of formula (Ia), optionally in combination with one or more topically acceptable diluents or carriers.

[0105] Compounds of formula (Ia) that are active when given orally can be formulated as liquids or solids, for example as syrups, suspensions, emulsions, tablets, capsules, or lozenges.

[0106] Liquid formulations typically consist of a suspension or solution of the compound of formula (Ia) in a suitable liquid carrier. Preferably, the carrier is non-aqueous, such as polyethylene glycol or oil. The formulation may also contain a suspending agent, a preservative, a flavoring agent, and / or a coloring agent.

[0107] A composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier normally used for preparing solid formulations, such as magnesium stearate, starch, lactose, sucrose, and cellulose.

[0108] A composition in the form of a capsule can be prepared using conventional encapsulation procedures, for example, pellets containing the active ingredient can be prepared using standard carriers and then filled into hard gelatin capsules; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier, for example, aqueous gums, celluloses, silicates, or oils, and then the dispersion or suspension can be filled into soft gelatin capsules.

[0109] A typical parenteral composition will consist of a solution or suspension of the compound of Formula (Ia) in a sterile aqueous carrier or parenterally acceptable oil, such as polyethylene glycol, polyvinylpyrrolidone, lecithin, peanut oil, or sesame oil. Alternatively, the solution can be lyophilized and then reconstituted with a suitable solvent just prior to administration.

[0110] Conveniently, compositions for nasal administration can be formulated as aerosols, droplets, gels, and powders. Aerosol formulations typically contain a solution or fine suspension of a compound of formula (Ia) in a pharmaceutically acceptable aqueous or non-aqueous solvent, and are usually provided in single or multiple doses in a sterile form in a sealed container, which can be in the form of a cartridge or refill for use with an atomizing device. Alternatively, the sealed container can be a disposable dispensing device, such as a single-dose nasal inhaler or an aerosol dispenser equipped with a metered valve. When the dosage form includes an aerosol dispenser, it contains a propellant, which can be a compressed gas, for example, air, or an organic propellant such as a chlorofluorocarbon (CFC) or a hydrofluorocarbon (HFC). Aerosol dosage forms can also be in the form of a pump atomizer.

[0111] Topical administration to the lung can be achieved by use of an aerosol formulation, which typically contains the active ingredient suspended or dissolved in a suitable aerosol propellant, such as a chlorofluorocarbon (CFC) or hydrofluorocarbon (HFC).

[0112] Topical administration to the lung can also be achieved by use of non-pressurized formulations, such as aqueous solutions or suspensions. These can be administered by a nebulizer, for example, a handheld portable or home or hospital (i.e., non-portable) nebulizer. The formulation can include excipients such as water, buffers, tonicity adjusters, pH adjusters, surfactants, and cosolvents.

[0113] Topical administration to the lung may also be achieved by use of a dry powder formulation, which typically contains a topically acceptable diluent such as lactose, glucose, or mannitol (preferably lactose).

[0114] The compounds of the present invention can also be administered rectally in the form of suppositories or enemas, including, for example, aqueous or oily solutions, suspensions, emulsions, and foams. Such compositions are prepared according to standard procedures well known to those skilled in the art. For example, suppositories can be prepared by mixing the active ingredient with a conventional suppository base, such as cocoa butter or other glycerides. In this case, the drug is mixed with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, and therefore melts in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycol.

[0115] Typically, for compositions intended for topical administration to the eye in the form of eye drops or eye ointment, the total amount of the compounds of the invention will be from about 0.0001% to less than 4.0% (w / w).

[0116] Preferably, for topical intraocular administration, compositions administered in accordance with the present invention are formulated as solutions, suspensions, emulsions, and other dosage forms.

[0117] Compositions administered according to the present invention may also contain various other ingredients, including, but not limited to, tonicity agents, buffers, surfactants, stabilizing polymers, preservatives, cosolvents, and viscosity-increasing agents. A preferred pharmaceutical composition of the present invention comprises a compound of the present invention formulated with a tonicity agent and a buffer. The pharmaceutical composition of the present invention may further optionally contain a surfactant and / or emollient and / or stabilizing polymer.

[0118] Various tonicity adjusting agents can be utilized to adjust the tonicity of the composition, preferably to that of natural tears for ophthalmic compositions. For example, sodium chloride, potassium chloride, magnesium chloride, calcium chloride, monosaccharides such as dextrose, fructose, and galactose, and / or simple polyols such as the sugar alcohols mannitol, sorbitol, xylitol, lactitol, isomaltitol, and maltitol, and hydrogenated starch hydrolysates can be added to the composition to approximate physiological tonicity. The amount of such tonicity adjusting agents will vary depending on the specific agent being added. However, generally, the composition will contain a sufficient amount of tonicity adjusting agent to provide the final composition with an ophthalmically acceptable osmolality (usually about 150-450 mOsm, preferably 250-350 mOsm, and most preferably about 290 mOsm). Generally, the tonicity adjusting agent of the present invention is present in the range of 2-4% w / w. Preferred tonicity agents of the present invention include monosaccharides or sugar alcohols, such as D-mannitol.

[0119] An appropriate buffer system (e.g., sodium phosphate, sodium acetate, sodium citrate, sodium borate, or boric acid) can be added to the composition to prevent pH drift under storage conditions. Specific concentrations will vary depending on the agent used. Preferably, however, the buffer is selected to maintain a target pH within the range of pH 5-8, more preferably a target pH of pH 5-7.

[0120] Surfactants can optionally be used to deliver higher concentrations of the compounds of the present invention. Surfactants act to solubilize the compounds and stabilize colloidal dispersions, such as micellar solutions, microemulsions, emulsions, and suspensions. Examples of surfactants that can be optionally used include polysorbates, poloxamers, polyosyl 40 stearate, polyoxyl castor oil, tyloxapol, Triton, and sorbitan monolaurate. Preferred surfactants for use in the present invention have a hydrophilic-lipophilic balance (HLB) in the range of 12.4 to 13.2 and are acceptable for ophthalmic use, such as Triton X114 and tyloxapol.

[0121] An additional agent that can be added to ophthalmic compositions of the compounds of the present invention is a demulcent, which acts as a stabilizing polymer. The stabilizing polymer should be an ionic / charged example preferred for topical intraocular use, more specifically, a polymer that possesses a negative charge on its surface capable of exhibiting a zeta potential of (-)10 to 50 mV for physical stability, and that can form a dispersion in water (i.e., is water-soluble). A preferred stabilizing polymer of the present invention would be 0.1 to 0.5% w / w of a polyelectrolyte or polyelectrolytes from the family of crosslinked polyacrylates, such as Carbomer and Pemulen®, specifically Carbomer 974p (polyacrylic acid).

[0122] Other compounds can be added to the ophthalmic compositions of the compounds of the present invention to increase the viscosity of the carrier. Examples of viscosity-increasing agents include, but are not limited to, hyaluronic acid and its salts, chondroitin sulfate and its salts, polysaccharides such as dextran, various polymers of the cellulose family, vinyl polymers, and acrylic acid polymers.

[0123] Topical ophthalmic products are typically packaged in multi-dose form. Therefore, preservatives are required to prevent microbial contamination during use. Suitable preservatives include: benzalkonium chloride, chlorobutanol, benzododecinium bromide, methylparaben, propylparaben, phenylethyl alcohol, edetate disodium, sorbic acid, polyquaternium-1, or other agents known to those skilled in the art. Such preservatives are typically utilized at levels of 0.001 to 1.0% w / v. The unit dose compositions of the present invention are sterile but typically unpreserved. Therefore, such compositions generally do not contain preservatives.

[0124] Compositions suitable for buccal or sublingual administration include tablets, lozenges, and pastilles wherein the compound of formula (Ia) is formulated with a carrier such as sugar and acacia, tragacanth, or gelatin and glycerin.

[0125] Compositions suitable for transdermal administration include ointments, gels, and patches.

[0126] The composition may contain 0.1% to 100% by weight, for example, 10 to 60% by weight, of the compound of formula (Ia), depending on the method of administration. The composition may contain 0% to 99.9% by weight, for example, 40% to 90% by weight, of the carrier, depending on the method of administration. The composition may contain 0.05 mg to 1000 mg, for example, 1.0 mg to 500 mg, for example, 1.0 mg to 50 mg, for example, about 10 mg, of the compound of formula (Ia), depending on the method of administration. The composition may contain 50 mg to 1000 mg, for example, 100 mg to 400 mg of the carrier, depending on the method of administration. The dosage of the compound used in the treatment of the aforementioned disorders will vary in the usual manner depending on the severity of the disorder, the weight of the patient, and other similar factors. However, as a general guide, a suitable unit dose may be 0.05 to 1000 mg, more preferably 1.0 to 500 mg, for example, 1.0 mg to 50 mg, for example, about 10 mg, and such a unit dose may be administered multiple times daily, for example, two or three times daily. Such therapy may extend for several weeks or months.

[0127] In one embodiment of the present invention, the compound of formula (Ia) is used in combination with additional therapeutic agent(s).When the compound of formula (Ia) is used in combination with other therapeutic agents, the compounds can be administered either sequentially or simultaneously by any convenient route.Alternatively, the compounds can be administered separately.

[0128] When the compounds of formula (Ia) are used to treat or prevent inflammatory diseases or diseases associated with an undesired immune response, therapeutic agents that may be used in combination with the compounds of formula (Ia) include: Corticosteroids (glucocorticoids), retinoids (e.g., acitretin, isotretinoin, tazarotene), anthralin, vitamin D analogs (e.g., cacitriol, calcipotriol), calcineurin inhibitors (e.g., tacrolimus, pimecrolimus), phototherapy or photochemotherapy (e.g., psoralen ultraviolet radiation, PUVA) or other forms of ultraviolet radiation therapy, cyclosporine, thiopurines (e.g., azathioprine, 6-mercaptopurine), methotrexate, anti-TNFα agents (e.g., infliximab, etanercept, adalimumab, certolizumab, golimumab, and biosimilars), phosphodiesterase-4 (PDE4) inhibitors (e.g., apremilast, crisaborole), anti-IL-17 agents (e.g., brodalumab, ixekizumab, secukinumab), anti-IL-12 / IL-23 agents (e.g., ustekinumab, briakinumab), anti-IL-23 agents (e.g., guselkumab, tildrakizumab), JAK (Janus kinase) inhibitors (e.g., tofacitinib, ruxolitinib, baricitinib, filgotinib, upadacitinib), plasma exchange, intravenous immunoglobulin (IVIG), cyclophosphamide, anti-CD20 B-cell depleting agents (e.g., rituximab, ocrelizumab, ofatumumab, obinutuzumab), anthracycline analogs (e.g., mitoxantrone), cladribine, sphingosine 1-phosphate receptor modulators or sphingosine analogs (e.g., fingolimod, siponimod, ozanimod, etrasimod), interferon beta preparations (including interferon beta 1b / 1a), glatiramer, anti-CD3 therapy (e.g., OKT3), anti-CD52 targeted agents (e.g., alemtuzumab), leflunomide, teriflunomide, gold compounds, laquinimod, potassium channel blockers (e.g., dalfampicin, benzodiazepine / 4-aminopyridine), mycophenolic acid, mycophenolate mofetil, purine analogs (e.g., pentostatin), mTOR (target of rapamycin) pathway inhibitors (e.g., sirolimus, everolimus), antithymocyte globulin (ATG), IL-2 receptor (CD25) inhibitors (e.g., basiliximab, daclizumab), anti-IL-6 receptor or anti-IL-6 agents (e.g., tocilizumab, siltuximab),Bruton's tyrosine kinase (BTK) inhibitors (e.g., ibrutinib), tyrosine kinase inhibitors (e.g., imatinib), ursodeoxycholic acid, hydroxychloroquine, chloroquine, B-cell activating factor (BAFF, also known as BlyS, B-lymphocyte stimulating factor) inhibitors (e.g., belimumab, blissibimod), other B-cell targeted therapies including fusion proteins targeting both APRIL (proliferation-inducing ligand) and BlyS (e.g., atacicept), pan-inhibitors or PIs including those targeting p110δ- and / or p110γ-containing isoforms 3K inhibitors (e.g., idelalisib, copanlisib, duvelisib), interferon α receptor inhibitors (e.g., anifrolumab, sifalimumab), T-cell costimulation blockers (e.g., abatacept, belatacept), thalidomide and its derivatives (e.g., lenalidomide), dapsone, clofazimine, leukotriene antagonists (e.g., montelukast), theophylline, anti-IgE therapy (e.g., omalizumab), anti-IL-5 agents (e.g., mepolizumab, reslizumab), long-acting muscarinic agents (e.g., tiotropium, acridil, dinium, umeclidinium), PDE4 inhibitors (e.g., roflumilast), riluzole, free radical scavengers (e.g., edaravone), proteasome inhibitors (e.g., bortezomib), complement cascade inhibitors including those directed against C5 (e.g., eculizumab), immunoadsorbents, antithymocyte globulin, 5-aminosalicylates and their derivatives (e.g., sulfasalazine, balsalazide, mesalamine), antiintegrin agents including those targeting α4β1 and / or α4β7 integrins (e.g., natalizumab, vedolizumab ), anti-CD11-α agents (e.g., efalizumab), nonsteroidal anti-inflammatory drugs (NSAIDs) including salicylates (e.g., aspirin), propionic acids (e.g., ibuprofen, naproxen), acetates (e.g., indomethacin, diclofenac, etodolac), oxicams (e.g., meloxicam), and fenamic acids (e.g., mefenamic acid), selective or relatively selective COX-2 inhibitors (e.g., celecoxib, etroxicoxib, valdecoxib, and etodolac, meloxicam, nabumetone), colchicine,These include IL-4 receptor inhibitors (e.g., dupilumab), topical / contact immunotherapy (e.g., diphenylcyclopropenone, squaric acid dibutyl ester), anti-IL-1 receptor therapy (e.g., anakinra), IL-1β inhibitors (e.g., canakinumab), IL-1 neutralization therapy (e.g., rilonacept), chlorambucil, certain antibiotics with immunomodulatory properties and / or the ability to modulate NRF2 (e.g., minocycline, tetracyclines including clindamycin, macrolide antibiotics), antiandrogen therapy (e.g., cyproterone, spironolactone, finasteride), pentoxifylline, ursodeoxycholic acid, obeticholic acid, fibrates, cystic fibrosis transmembrane conductance regulator (CFTR) modulators, VEGF (vascular endothelial growth factor) inhibitors (e.g., bevacizumab, ranibizumab, pegaptanib, aflibercept), pirfenidone, and mizoribine. ,

[0129] When the compound of formula (Ia) is used to treat or prevent cancer, the therapeutic agent that can be used in combination with the compound of formula (Ia) includes an active agent used in combination with cancer therapy, such as a drug used as a palliative treatment to improve undesired side effects.Therefore, in one embodiment, the additional therapeutic agent is a drug used as a palliative treatment, such as an antiemetic, a drug intended to relieve pain, such as an opioid, a drug used to reduce high blood uric acid levels, such as allopurinol or rasburicase, an antidepressant, a sedative, an anticonvulsant, a laxative, an antidiarrheal, and / or an antacid.

[0130] In another embodiment, the additional therapeutic agent is an additional cancer treatment such as chemotherapy, targeted therapy, immunotherapy, and hormonal therapy.

[0131] Examples of chemotherapeutic agents include antimetabolites (e.g., folic acid, purine, and pyrimidine derivatives) and alkylating agents (e.g., nitrogen mustards, nitrosoureas, platinum, alkylsulfonates, hydrazines, triazenes, aziridines, spindle poisons, cytotoxic agents, toposimerase inhibitors, and others). In one embodiment, the additional therapeutic agent is a chemotherapeutic agent, such as aclarubicin, actinomycin, alitretinone, altretamine, aminopterin, aminolevulinic acid, amrubicin, amsacrine, anagrelide, arsenic trioxide, asparaginase, atrasentan, belotecan, bexarotene, endamustine, bleomycin, bortezomib, busulfan, camptothecin, capecitabine, carboplatin, latin, carboquone, carmofur, carmustine, celecoxib, chlorambucil, chlormethine, cisplatin, cladribine, clofarabine, crisantaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, decitabine, demecolcine, docetaxel, doxorubicin, efaproxiral, elesclomol, elsamitrucin, enocitabine, epirubicin, estramustine, etoglucide, etoposide, Loxuridine, fludarabine, fluorouracil (5FU), fotemustine, gemcitabine, gliadel implant, hydroxycarbamide, hydroxyurea, idarubicin, ifosfamide, irinotecan, irofulven, ixabepilone, larotaxel, leucovorin, liposomal doxorubicin, liposomal daunorubicin, lonidamine, lomustine, lucanthone, mannosulfan, masoprocol, melphalan, mercaptopurine, mesna, meth Trexate, methyl aminolevulinate, mitobronitol, mitoguazone, mitotane, mitomycin, mitoxantrone, nedaplatin, nimustine, oblimersen, omacetaxine, ortataxel, oxaliplatin, paclitaxel, pegaspargase, pemetrexed, pentostatin, pirarubicin, pixantrone, plicamycin, porfimer sodium, prednimustine, procarbazine, raltitrexed, ranimustine, rubitecan,The compound is selected from the group consisting of sapacitabine, semustine, citimagine seradenovec, satraplatin, streptozocin, talaporfin, tegafur-uracil, temoporfin, temozolomide, teniposide, tesetaxel, testolactone, tetranitrate, thiotepa, tiazofurin, thioguanine, tipifarnib, topotecan, trabectedin, triazicon, triethylenemelamine, triplatin, tretinoin, treosulfan, trofosfamide, uramustine, valrubicin, verteporfin, vinblastine, vincristine, vindesine, vinfhmine, vinorelbine, vorinostat, and zorubicin.

[0132] Examples of targeted therapy include tyrosine kinase inhibitors, cyclin-dependent kinase inhibitors, monoclonal antibodies, and fusion proteins.In one embodiment, the additional therapeutic agent is selected from the group consisting of axitinib, bosutinib, cediranib, dasatinib, erlotinib, imatinib, gefitinib, lapatinib, lestaurtinib, nilotinib, semaxanib, sorafenib, sunitinib, vandetanib, alvocidib, seliciclib, herceptin, rituximab, tositumomab, cetuximab, panitumumab, trastuzumab, alemtuzumab, bevacizumab, edrecolomab, gemtuzumab, aflibercept, denileukin diftitox, and bexar.

[0133] When a compound of Formula (Ia) is used to treat or prevent obesity, therapeutic agents that may be used in combination with the compound of Formula (Ia) include gastric or pancreatic lipase inhibitors (e.g., orlistat); lipid-lowering agents (e.g., statins, fibrates, niacin, or derivatives thereof (e.g., acipimox), lecithin, bile acid sequestrants, ezetimibe, lomitapide, phytosterols, omega-3 supplements, PCSK9 inhibitors); CB-1 antagonists; lipoxygenase inhibitors; somostatin analogs; insulin compounds or insulin analogs (e.g., human insulin, insulin lispro, insulin aspart, insulin glulisine, insulin glargine, insulin degludec); insulin sensitizers such as PPAR-γ agonists, PPAR-α agonists, or mixed PPAR-γ / α agonists (e.g., metformin, pioglitazone, or rosiglitazone); insulin secretagogues (e.g., nateglinide or repaglinide, or sulfonylureas such as gliclazide, glimeperide, limepiride, glyburide); SGLT2 inhibitors (e.g., dapagliflozin, canagliflozin, or empagliflozin); amylin analogs (e.g., pramlintide); DPPIV inhibitors (e.g., sitagliptin, saxagliptin, linagliptin, alogliptin, or vildagliptin); GLP-1 agonists (e.g., albiglutide, dulaglutide, exenatide, liraglutide, semaglutide, or lixisenatide); alpha-glucosidase inhibitors (e.g., acarbose, miglitol, or voglibose); phosphodiesterase inhibitors (e.g., pentoxifylline); glycogen phosphorylase inhibitors; MCH-1 antagonists; glucokinase activators; glucagon antagonists; insulin signaling agonists; PTP1B inhibitors; gluconeogenesis inhibitors; GSK inhibitors, or galanin receptor agonists.

[0134] When the compound of formula (Ia) is used to treat or prevent a diabetic disease, therapeutic agents that may be used in combination with the compound of formula (Ia) include gastric or pancreatic lipase inhibitors (e.g., orlistat); lipid-lowering agents (e.g., statins, fibrates, niacin, or derivatives thereof (e.g., acipimox), lecithin, bile acid sequestrants, ezetimibe, lomitapide, phytosterols, omega-3 supplements, PCSK9 inhibitors); CB-1 antagonists; lipoxygenase inhibitors; somostatin analogs; insulin compounds or insulin analogs (e.g., human insulin, insulin lispro, insulin aspart, insulin glulisine, insulin glargine, insulin degludec); insulin sensitizers such as PPAR-γ agonists, PPAR-α agonists, or mixed PPAR-γ / α agonists (e.g., metformin, pioglitazone, or rosiglitazone); insulin secretagogues (e.g., nateglinide or repaglinide, or sulfonylureas such as gliclazide, glimeperide, limepiride, glyburide); SGLT2 inhibitors (e.g., dapagliflozin, canagliflozin, or empagliflozin); amylin analogs (e.g., pramlintide); DPPIV inhibitors (e.g., sitagliptin, saxagliptin, linagliptin, alogliptin, or vildagliptin); GLP-1 agonists (e.g., albiglutide, dulaglutide, exenatide, liraglutide, semaglutide, or lixisenatide); alpha-glucosidase inhibitors (e.g., acarbose, miglitol, or voglibose); phosphodiesterase inhibitors (e.g., pentoxifylline); glycogen phosphorylase inhibitors; MCH-1 antagonists; glucokinase activators; glucagon antagonists; insulin signaling agonists; PTP1B inhibitors; gluconeogenesis inhibitors; GSK inhibitors, or galanin receptor agonists.

[0135] Compounds of formula (Ia) have the following desirable properties: Low EC that activates PKM250 value and / or high E max value; Low EC that activates PKLR 50 value and / or high E max value; Low EC that activates PKM2 and PKLR 50 value and / or high E max value; Low IC, which reduces cell proliferation 50 value; Reduced dose and dosing frequency due to improved pharmacokinetics; Improved oral systemic bioavailability; Decreased plasma clearance after intravenous administration; Enhanced cell permeability; Low toxicity at appropriate therapeutic doses may indicate one or more of:

[0136] (abbreviation) [Table 1] TIFF2025538980000032.tif244170TIFF2025538980000033.tif174170 [Example]

[0137] (Example) (analytical equipment) NMR spectra were recorded using a Bruker 400 MHz Avance III spectrometer fitted with a BBFO 5 mm probe or a Bruker 500 MHz Avance III HD spectrometer equipped with a Bruker 5 mm SmartProbe™. Spectra were measured at 298 K and referenced to the solvent resonance unless otherwise indicated. Chemical shifts are reported in parts per million. Data were acquired using Bruker TopSpin software.

[0138] LCMS analysis was performed on an Agilent LCMS system using either a Waters Acquity CSH C18 (4.6 × 30 mm) or BEH C18 column (4.6 × 30 mm), maintained at a temperature of 40 °C and eluted at a constant flow rate of 2.5 mL / min over 4 or 15 min with a linear acetonitrile gradient appropriate for the lipophilicity of the compound. The aqueous portion of the mobile phase was either 0.1% formic acid (CSH C18 column) or 10 mM ammonium bicarbonate (BEH C18 column). LC-UV chromatograms were recorded at 254 nm using an Agilent VWD or DAD detector. Mass spectra were recorded using an Agilent MSD detector with electrospray ionization switched between positive and negative ion modes. Sample concentrations were adjusted to obtain an appropriate UV response.

[0139] (Preparative HPLC purification method) (Acidic method (A):) The product was dissolved in DMSO (mL), filtered, and purified by reverse-phase preparative HPLC (Waters 2767 Sample Manager, Waters 2545 Binary Gradient Module, Waters Systems Fluidics Organizer, Waters 515 ACD Pump, Waters 515 Makeup Pump, Waters 2998 Photodiode Array Detector, Waters Qda) using a Waters X-SELECT CSH C18 ODB preparative column, 130 Å, 5 μm, 30 mm × 100 mm, flow rate 40 mL / min, eluted with a 0.1% formic acid-MeCN gradient in water over 12.5 min. An at-column dilution pump provided 2 mL / min of MeCN throughout the process, which is included in the MeCN percentages below. Gradient information: 0.0-0.5 min, lp% MeCN; 0.5-10.5 min, increase from lp% MeCN to fp% MeCN; 10.5-10.6 min, increase from fp% MeCN to 100% MeCN; 10.6-12.5 min, hold at 100% MeCN. Clean fractions were evaporated in a Genevac.

[0140] (Basic Method (B):) The product was dissolved in DMSO (0.5 mL), filtered, and purified by reverse-phase preparative HPLC on a Waters X-Bridge BEH C18 ODB preparative column, 130 Å, 5 μm, 30 mm × 100 mm, at a flow rate of 40 mL / min, eluting with a 0.3% ammonia-MeCN gradient in water over 12.5 min using UV detection over the entire wavelength range by PDA and QDA and ELS detectors. An at-column dilution pump provided 2 mL / min of MeCN throughout the procedure, which included the following MeCN percentages: Gradient information: 0.0–0.5 min, 20% MeCN; 0.5–10.5 min, ramp from 20% MeCN to 50% MeCN; 10.5–10.6 min, ramp from 50% MeCN to 100% MeCN; 10.6–12.5 min, hold at 100% MeCN. Clean fractions were evaporated in a Genevac.

[0141] Alternatively, the following analytical LCMS equipment and methods were also used: [Table 2]

[0142] (Commercially available materials) All starting materials and solvents were either obtained from commercial suppliers or prepared according to literature references.

[0143] (General method) All reactions were stirred unless otherwise noted. Organic solutions were dried over anhydrous magnesium sulfate by conventional methods. Hydrogenations were carried out in gas autoclaves (bombs) under specified conditions or under pressure in a Thales H-cube flow reactor.

[0144] (Synthesis of intermediates) (Intermediate 1: 6-(chloromethyl)-2,3-dihydropyrazolo[5,1-b]oxazole) [ka] (Process 1) To a mixture of ethyl 5-hydroxy-1H-pyrazole-3-carboxylate (1 g, 6.4 mmol) and 1,2-dibromoethane (1302 mg, 7 mmol) in MeCN (5 mL) was added K2CO3 (1.9 g, 14 mmol) at 0 °C. The reaction was stirred at room temperature for 5 h. After LCMS showed the reaction was complete, water (10 mL) was added to the reaction mixture. The mixture was extracted with EtOAc (10 mL × 3). The organic layer was concentrated under reduced pressure at 40 °C. The residue was purified by flash column chromatography (12 g, petroleum ether / tert-butyl methyl ether = 100:0 to 40:60) to give ethyl 2,3-dihydropyrazolo[5,1-b]oxazole-6-carboxylate (800 mg, 100% purity) as a yellow solid. MS (ES+): 183.3 (M+H)+.

[0145] (Process 2) To a solution of ethyl 2,3-dihydropyrazolo[5,1-b]oxazole-6-carboxylate (800 mg, 4.4 mmol) in THF (10 mL) was added LAH (2.8 mL, 5.7 mmol, 2 M solution in THF) at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. After LCMS showed the reaction was complete, water (10 mL) was added to the mixture and extracted with EtOAc (10 mL × 3). The organic layer was concentrated under reduced pressure at 40 °C. The residue was purified by flash column chromatography (20 g, petroleum ether / tert-butyl methyl ether = 100:00 to 20:80) to give (2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)methanol (260 mg, 100% purity) as a yellow solid. MS(ES+): 141.4(M+H)+.

[0146] (Step 3) To a solution of (2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)methanol (200 mg, 1.43 mmol) in DCM (5 mL) was added SOCl (221 mg, 1.8 mmol) at 0 °C, and the reaction mixture was stirred at room temperature for 0.5 h. After LCMS showed the reaction was complete, the mixture was concentrated under reduced pressure at 30 °C to remove DCM and most of the excess SOCl. The residue was quenched with ice water (10 mL), adjusted to pH = 9 with 2N aqueous KCO solution, and extracted with DCM (10 mL × 3). The organic layer was washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure at 30 °C to give the title compound (200 mg, 100% purity) as a yellow oil, which was used directly in the next step without further purification. MS (ES): 159.3 (M+H)

[0147] (Intermediate 2: 6-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)thio)phthalazin-1(2H)-one) [ka] A suspension of 6-mercaptophthalazin-1(2H)-one (1.26 g, 80 wt%, 1 equiv, 5.66 mmol), 4-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (1.82 g, 95 wt%, 1.1 equiv, 6.22 mmol), KCO (1.56 g, 2.0 equiv, 11.3 mmol), and 1,10-phenanthroline (408 mg, 0.4 equiv, 2.26 mmol) in DMF (28.0 mL) was purged with N for 10–15 min, followed by the addition of copper(I) iodide (215 mg, 0.2 equiv, 1.13 mmol). The reaction mixture was purged with N for 10 min and then heated at 100 °C overnight. The reaction was cooled to RT and poured into a mixture of ice and water, resulting in the formation of a precipitate which was filtered and washed with water (50 mL). The resulting dark brown gummy solid was dissolved in DCM (250 mL) and washed with semi-concentrated brine (200 mL). The organics were dried (MgSO), filtered, and concentrated under reduced pressure to give a solid (1.87 g). The crude material was combined with a crude mixture (1.63 g) from a separate experiment, dissolved in DCM (20 mL) and MeOH (2 mL), concentrated onto silica, and purified by chromatography to give the title compound (982.9 mg, 2.9 mmol) as a light brown solid. MS (ES) + ): 195.1(M+H)+.

[0148] (Intermediate 3: 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-thiol) [ka] (Process 1) To a solution of 4-iodo-1H-pyrazole (80 g, 412 mmol) and 3,4-dihydro-2H-pyran (54 g, 618 mmol) in MeCN (1.2 L) was added TsOH (708 mg, 4.2 mmol) at RT. The reaction mixture was stirred at 85° C. for 16 h. After LCMS showed the reaction was complete, the mixture was concentrated under reduced pressure at 45° C. The residue was purified by flash column chromatography to give 4-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (100 g) as a white solid. MS (ES) + ): 279.2(M+H) +

[0149] (Process 2) To a solution of 4-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (100 g, 360 mmol), 2-ethylhexyl 3-mercaptopropanoate (94 g, 432 mmol), Pd2dba3 (13 g, 14.4 mmol), and Xantphos (16.6 g, 28.8 mmol) in DMF (1 L) was added DIPEA (140 g, 1080 mmol) at RT. The reaction mixture was stirred at 100 °C for 16 h. After LCMS showed the reaction was complete, the mixture was extracted with EtOAc (600 mL × 3) and concentrated under reduced pressure at 45 °C. The residue was purified by flash column chromatography to give 2-ethylhexyl 3-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)thio)propanoate (116 g) as a yellow oil. MS (ES) + ): 369.3(M+H) +

[0150] (Step 3) To a mixture of 2-ethylhexyl 3-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)thio)propanoate (116 g, 315 mmol) in THF (2 L) was added NaOEt (252 mL, 630 mmol, 2.5 M solution in EtOH) at 0° C. The reaction was stirred at 0° C. for 0.5 h. After LCMS showed the reaction was complete, the reaction mixture was quenched with HCl (1 M) until the pH was 6. The mixture was extracted with EtOAc (600 mL × 3). The organic layer was concentrated under reduced pressure at 40° C. and purified by flash column chromatography to give 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-thiol (45 g) as an oil, which was used in the next step without further purification. MS (ES) + ): 101.4(M+H) +

[0151] (Intermediate 4: 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-thiol) [ka] (Process 1) To a solution of 3-iodo-1H-pyrazole (5.0 g, 25.8 mmol) and 3,4-dihydro-2H-pyran (3.3 g, 38.7 mmol) in MeCN (50 mL) was added p-TsOH (43 mg, 0.3 mmol) at room temperature, and the reaction mixture was stirred at 80 °C for 16 h. After LCMS showed the reaction was complete, the reaction mixture was concentrated under reduced pressure at 45 °C. The residue was purified by flash column chromatography (25 g, petroleum ether / tert-butyl methyl ether = 100:0 to 90:10) to give 3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (6.6 g, 100% purity) as a yellow oil. MS (ES) + ): 279.1(M+H)+.

[0152] (Process 2) To a solution of 3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (6.6 g, 23.7 mmol), 2-ethylhexyl 3-mercaptopropanoate (6.7 g, 30.8 mmol), Pd2dba3 (540 mg, 0.59 mmol), and Xantphos (685 mg, 1.19 mmol) in DMF (100 mL) was added DIPEA (9.2 g, 71.1 mmol) at room temperature. The reaction mixture was stirred at 100 °C for 16 h. After LCMS showed the reaction was complete, water (50 mL) was added, and the mixture was extracted with EtOAc (50 mL × 3). The combined organic layers were concentrated under reduced pressure at 45 °C. The residue was purified by flash column chromatography (120 g, petroleum ether / tert-butyl methyl ether = 100:00 to 80:20) to give 2-ethylhexyl 3-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)thio)propanoate (7.1 g, 44.18% purity) as a yellow oil. MS (ES) + ): 369.3(M+H) +

[0153] (Step 3) To a mixture of 2-ethylhexyl 3-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)thio)propanoate (7.1 g, 19.3 mmol) in THF (150 mL) was added EtONa (15 mL, 2.5 M solution in EtOH) at 0° C. The reaction was stirred at 0° C. for 0.5 h. After LCMS showed the reaction was complete, the pH of the reaction mixture was adjusted by careful addition of aqueous HCl (1 M) until pH=6. The mixture was extracted with EtOAc (800 mL×3). The organic layer was concentrated under reduced pressure at 40° C. The residue was purified by flash column chromatography (40 g, petroleum ether / tert-butyl methyl ether = 100:0 to 60:40) to give 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-thiol (2.8 g, 100% purity) as a yellow oil. MS (ES) + ): 185.3(M+H)+.

[0154] Intermediate 5: (4-chloro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methanol [ka] (Process 1) A mixture of ethyl 5-methyl-1H-pyrazole-3-carboxylate (2.0 g, 12.97 mmol) and NCS (2.42 g, 18.16 mmol) in DMF (30 mL) was stirred at room temperature for 1 h. After LCMS showed the reaction was complete, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (50 mL × 4). The organic layer was washed with saturated aqueous NH4Cl (100 mL × 2), concentrated, and purified by flash column chromatography (40 g, petroleum ether / tert-butyl methyl ether = 100:00 to 20:80) to give ethyl 4-chloro-5-methyl-1H-pyrazole-3-carboxylate (2.0 g, 68% purity) as a white solid. MS (ES) + ): 189.1(M+H)+.

[0155] (Process 2) A mixture of ethyl 4-chloro-5-methyl-1H-pyrazole-3-carboxylate (2.0 g, 5.30 mmol), 3,4-dihydro-2H-pyran (892 mg, 10.6 mmol), and 4-methylbenzenesulfonic acid (86 mg, 0.5 mmol) in MeCN (15 mL) was stirred at 70 °C overnight. After LCMS showed the reaction was complete, the reaction mixture was concentrated to remove MeCN. The crude product was purified by flash column chromatography (20 g, petroleum ether / tert-butyl methyl ether = 100:00 to 85:15) to give ethyl 4-chloro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylate (760 mg, 79% purity) as a yellow oil. MS (ES) + ): 189.2(M+H)+.

[0156] (Step 3) To a solution of ethyl 4-chloro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylate (760 mg, 2.79 mmol) in THF (4 mL) was added LiBH (5.6 mL, 5.60 mmol, 1 M in THF), and the reaction mixture was stirred at room temperature for 4 hours. After LCMS showed the reaction was complete, the reaction mixture was quenched with saturated aqueous NH Cl until gas evolution subsided. The suspension was extracted with DCM (50 mL × 4). The organic layer was then dried over Na SO , filtered, and concentrated under reduced pressure at 40 °C to give the title product (540 mg, 86% purity) as a white solid. MS (ES) + ): 231.2(M+H)+.

[0157] (Intermediate 6: 6-mercapto-2-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methyl)phthalazin-1(2H)-one) [ka] (Process 1) A suspension of 6-bromophthalazin-1(2H)-one (2.117 g, 98 wt%, 1 equiv, 9.217 mmol) and cesium carbonate (6.006 g, 2.0 equiv, 18.43 mmol) in DMF (40 mL) was stirred at 80° C. for 1 h and then allowed to cool to RT. A solution of 3-(chloromethyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (2.055 g, 9.217 mmol) in DMF (10 mL) was added, and the reaction mixture was stirred at RT for 20 h. EtOAc (150 mL) was added, and the reaction mixture was washed with water (100 mL). The organic layer was collected, and the aqueous was extracted with EtOAc (3×100 mL). The combined organic extracts were washed with 50% brine (2×100 mL), brine (100 mL), and concentrated in vacuo to give the crude product. The crude product was purified by chromatography on silica gel to give 6-bromo-2-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methyl)phthalazin-1(2H)-one (Intermediate 6A, 2.192 g) as an off-white solid. MS (ES)+ ): 389 / 391(M+H)+.

[0158] (Process 2) A solution of 6-bromo-2-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methyl)phthalazin-1(2H)-one (1.47 g, 3.40 mmol) in DMF (30 mL) was sparged with N for 5 min. DIPEA (879 mg, 1.18 mL, 2.00 equiv, 6.80 mmol), Xantphos (197 mg, 340 μmol), Pd(dba) (156 mg, 170 μmol), and 2-ethylhexyl 3-mercaptopropanoate (852 mg, 3.90 mmol) were added sequentially, and the reaction mixture was stirred at 100 °C for 90 min. 2-Ethylhexyl 3-mercaptopropanoate (0.20 mL, 0.876 mmol) was added, and the mixture was stirred at 100 °C for 90 min. The reaction mixture was concentrated in vacuo, and the residue was azeotroped with toluene (three times) to give the crude product. The crude product was purified by chromatography on silica gel to give 2-ethylhexyl 3-((1-oxo-2-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methyl)-1,2-dihydrophthalazin-6-yl)thio)propanoate (1.648 g) as a dark yellow oil. MS (ES) + ): 527(M+H) + .

[0159] (Step 3) A stirred solution of 2-ethylhexyl 3-((1-oxo-2-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methyl)-1,2-dihydrophthalazin-6-yl)thio)propanoate (1.64 g, 2.77 mmol) in THF (25 mL) was treated dropwise with sodium ethoxide (2.13 g, 6.56 mmol). The reaction mixture was stirred at room temperature for 1 h and then diluted with DCM (100 mL) and saturated aqueous NH4Cl (100 mL). The organic layer was collected and the aqueous was extracted with DCM (2 x 50 mL). The combined organic extracts were washed with 50% brine (50 mL), dried (phase separator), and concentrated in vacuo to give the crude product. The crude product was purified by chromatography on silica gel to give the title compound (715 mg) as a pale pink solid. [ka]

[0160] (Intermediate 7: 6-mercaptophthalazin-1(2H)-one) [ka] A mixture of 6-bromophthalazin-1(2H)-one (0.60 g, 1 equiv., 2.7 mmol), 2-ethylhexyl 3-mercaptopropanoate (0.61 g, 0.64 mL, 1.05 equiv., 2.8 mmol), cesium carbonate (1.7 g, 2 equiv., 5.3 mmol), Xantphos (0.15 g, 0.1 equiv., 0.27 mmol), and Pd2(dba)3 (0.12 g, 0.05 equiv., 0.13 mmol) in DMF (12 mL) was heated to 100 °C for 12 h. After cooling to RT, the reaction mixture was diluted with water (50 mL) and then extracted with DCM (20 mL). The aqueous layer was acidified with 1 M HCl and then extracted with EtOAc (2 × 50 mL). The organic phase was collected, dried (MgSO4) and evaporated under reduced pressure to give the title compound (0.33g) as a sticky orange solid. MS(ES + ): 179(M+H) + .

[0161] (Intermediate 8: 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-iodo-1H-pyrazole) [ka] A mixture of 3-iodopyrazole (300 mg, 1 equiv., 1.55 mmol), (2-bromoethoxy)dimethyl-tert-butylsilane (407 mg, 366 μL, 1.1 equiv., 1.70 mmol), and potassium carbonate (321 mg, 1.5 equiv., 2.32 mmol) in MeCN (10.0 mL) was heated at 85° C. for 24 h. The reaction mixture was cooled to RT and diluted with DCM (10 mL), then filtered through Celite, washing further with DCM (20 mL) and MeOH (10 mL). The residue (oil and solid) was partitioned between EtOAc (20 mL) and water (10 mL). The organics were washed with brine (10 mL × 2), dried over MgSO4, and concentrated under reduced pressure to give the crude product as a clear yellow liquid (536 mg) containing a mixture of regioisomers. The crude material was dissolved in DCM (5 mL), concentrated onto silica and purified by chromatography to give the title compound (108.5 mg) as a clear, colourless oil. [ka]

[0162] (Intermediate 9: 5-(chloromethyl)-2,3-dihydrofuro[3,2-b]pyridine) [ka] (Process 1) To a solution of methyl furo[3,2-b]pyridine-5-carboxylate (800 mg, 4.52 mmol) was added 10% Pd / C (320 mg, containing 50% water) in MeOH (10 mL), and the mixture was stirred under H at 25 °C for 10 h. After LCMS showed the reaction was complete, the mixture was dried over NaSO, filtered, and concentrated under reduced pressure at 30 °C, and the residue was purified by flash column chromatography to give methyl 2,3-dihydrofuro[3,2-b]pyridine-5-carboxylate (750 mg) as a yellow solid. MS (ES) + ): 180.3(M+H) + .

[0163] (Process 2) To a solution of methyl 2,3-dihydrofuro[3,2-b]pyridine-5-carboxylate (750 mg, 4.19 mmol) in THF (10 mL) was added Red-Al (2.42 g, 8.38 mmol, 70 wt % in toluene) at 0 °C, and the reaction mixture was stirred at RT for 2 h. After LCMS showed the reaction was complete, NH4Cl (1 mL) was added to the mixture. The mixture was quenched over Na2SO4, filtered, and concentrated under reduced pressure at 30 °C, and the residue was purified by flash column chromatography to give (2,3-dihydrofuro[3,2-b]pyridin-5-yl)methanol (360 mg) as a yellow solid. MS (ES) + ): 152.4(M+H) + .

[0164] (Step 3) To a solution of (2,3-dihydrofuro[3,2-b]pyridin-5-yl)methanol (140 mg, 0.93 mmol) in DCM (5 mL) was added SOCl (221 mg, 1.86 mmol) dropwise at 0 °C, and the reaction mixture was stirred at RT for 2 h. After LCMS showed the reaction was complete, the mixture was concentrated under reduced pressure at 30 °C to remove DCM and SOCl to give 5-(chloromethyl)-2,3-dihydrofuro[3,2-b]pyridine (150 mg) as a yellow oil, which was used directly in the next step. MS (ES) +): 170.4(M+H) + .

[0165] (Intermediate 10: 1-methyl-1H-pyrazole-4-thiol) [ka] (Process 1) A mixture of 4-iodo-1-methyl-1H-pyrazole (1.00 g, 1 equiv., 4.81 mmol), 2-ethylhexyl 3-mercaptopropanoate (1.05 g, 1.10 mL, 1 equiv., 4.81 mmol), DIPEA (684 mg, 921 μL, 1.1 equiv., 5.29 mmol), Pd2dba3 (220 mg, 0.05 equiv., 240 μmol), and Xantphos (278 mg, 0.1 equiv., 481 μmol) in DMF (25 mL) was stirred at 100° C. under nitrogen for 1.5 h and then allowed to cool to room temperature. Water and DCM were added, and the layers were separated. The organic layer was washed with water, brine, dried (MgSO4), and absorbed onto silica. The crude product was purified by chromatography on silica gel (40 g cartridge, 0-50% EtOAc / isohexane) to give 2-ethylhexyl 3-((1-methyl-1H-pyrazol-4-yl)thio)propanoate (1.27 g, 4.1 mmol, 85%, 96% purity) as a pale yellow oil. MS (ES) + ): 299(M+H) +

[0166] (Process 2) Sodium ethanolate (543 mg, 625 μL, 21 wt%, 2.5 equiv., 1.68 mmol) was added dropwise to a solution of 2-ethylhexyl 3-((1-methyl-1H-pyrazol-4-yl)thio)propanoate (200 mg, 1 equiv., 670 μmol) in THF (3.00 mL) at 0° C. under nitrogen, and the mixture was allowed to warm to room temperature and stirred for 20 min. 1 N HCl (1 mL) and DCM were added, and the layers were separated through a phase separator. The organic layer was washed with brine, dried (MgSO), and concentrated in vacuo to give the crude title compound as a pale yellow oil. The product was used in the next step without further purification.

[0167] (Example Synthesis) Example 1: 6-((1H-pyrazol-4-yl)sulfonyl)-2-((5-methoxypyridin-2-yl)methyl)phthalazin-1(2H)-one [ka] (Process 1) A mixture of 6-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)thio)phthalazin-1(2H)-one (Intermediate 2, 75.0 mg, 1 equiv., 228 μmol) and cesium carbonate (223 mg, 3 equiv., 685 μmol) in DMF (1.50 mL) was stirred at 70° C. for 30 min. 2-(Chloromethyl)-5-methoxypyridine hydrochloride (48.8 mg, 1.1 equiv., 25 μmol) was added and the mixture was stirred at room temperature overnight. Water and DCM were added and the layers were separated through a phase separator. The organic layer was washed with brine, dried (MgSO4), and concentrated in vacuo to give crude 2-((5-methoxypyridin-2-yl)methyl)-6-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)thio)phthalazin-1(2H)-one. The product was used in the next step without further purification. The yield was assumed to be quantitative.

[0168] (Process 2) A mixture of 2-((5-methoxypyridin-2-yl)methyl)-6-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)thio)phthalazin-1(2H)-one and oxone (309 mg, 2.2 equiv., 502 μmol) in DMF (1.50 mL) was stirred overnight. Saturated NaHCO and DCM were added and the layers were separated. The organic layer was washed with brine, dried (MgSO), and concentrated in vacuo to give a crude mixture of 2-((5-methoxypyridin-2-yl)methyl)-6-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)sulfonyl)phthalazin-1(2H)-one and 6-((1H-pyrazol-4-yl)sulfonyl)-2-((5-methoxypyridin-2-yl)methyl)phthalazin-1(2H)-one. The mixture was dissolved in MeOH (1.5 mL) and hydrogen chloride (4N in dioxane) (41.6 mg, 285 μL, 4.00 molar, 5 equiv, 1.14 mmol) was added. The mixture was stirred for 1 hour and then concentrated in vacuo. Saturated NaHCO, 2N NaOH, and DCM were added and the layers were separated. The organic layer was washed with brine and then absorbed onto silica. The crude product was purified by chromatography on silica gel (4 g cartridge, 0–50% of 10% (MeOH(0.7 M NH):DCM)):DCM) to afford 6-((1H-pyrazol-4-yl)sulfonyl)-2-((5-methoxypyridin-2-yl)methyl)phthalazin-1(2H)-one (40.8 mg, 98% purity) as a white solid. [ka]

[0169] Example 2: 2-((1H-pyrazol-3-yl)methyl)-6-((1-(difluoromethyl)-1H-pyrazol-4-yl)sulfonyl)phthalazin-1(2H)-one [ka] (Process 1) Nitrogen was bubbled through a mixture of 6-mercapto-2-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methyl)phthalazin-1(2H)-one (Intermediate 6, 150 mg, 91 wt%, 1 equiv., 399 μmol), 1-(difluoromethyl)-4-iodo-1H-pyrazole (126 mg, 1.3 equiv., 518 μmol), 1,10-phenanthroline (32.3 mg, 0.45 equiv., 179 μmol), and potassium carbonate (93.7 mg, 1.7 equiv., 678 μmol) in DMF (2.5 mL) for 5 minutes. Copper(I) iodide (16.7 mg, 0.22 equiv., 87.7 μmol) was added, and the mixture was stirred under nitrogen at 100° C. for 4 hours and then allowed to cool to room temperature. Water and EtOAc were added and the layers were separated. The organic layer was washed with brine and then absorbed onto silica. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc / isohexane) to afford 6-((1-(difluoromethyl)-1H-pyrazol-4-yl)thio)-2-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methyl)phthalazin-1(2H)-one (165 mg, 0.36 mmol, 99% purity) as a white solid. MS(ES+): 459(M+H)+

[0170] (Process 2) A mixture of 6-((1-(difluoromethyl)-1H-pyrazol-4-yl)thio)-2-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methyl)phthalazin-1(2H)-one (165 mg, 99 wt%, 1 equiv., 356 μmol) and oxone (482 mg, 2.2 equiv., 784 μmol) in DMF (1.5 mL) was stirred overnight. Saturated NaHCO and DCM were added, and the layers were separated through a phase separator. The organic layer was washed with brine, dried (MgSO), and concentrated in vacuo to give a crude mixture of 6-((1-methyl-1H-pyrazol-3-yl)sulfonyl)-2-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3yl)methyl)phthalazin-1(2H)-one and 2-((1H-pyrazol-3-yl)methyl)-6-((1-(difluoromethyl)-1H-pyrazol-4-yl)sulfonyl)phthalazin-1(2H)-one. The mixture was dissolved in MeOH (1.5 mL) and hydrogen chloride (4N in dioxane) (64.9 mg, 445 μL, 4.00 molar, 5 equivalents, 1.78 mmol) was added. The mixture was stirred for 1.5 hours and then concentrated in vacuo. Saturated NaHCO, 2N NaOH, and DCM were added and the layers were separated. The organic layer was washed with brine and then absorbed onto silica. The crude product was purified by chromatography on silica gel (4 g cartridge, 0-50% of 10% (MeOH (0.7 M NH):DCM)):DCM) to afford the title compound (48.5 mg, 99% purity) as a white solid. [ka]

[0171] Example 3: 2-((2,3-dihydrofuro[3,2-b]pyridin-5-yl)methyl)-6-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)sulfonyl)phthalazin-1(2H)-one [ka] (Process 1) A suspension of 6-mercaptophthalazin-1(2H)-one (Intermediate 7, 235 mg, 92 wt%, 1 equiv, 1.21 mmol), 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-iodo-1H-pyrazole (Intermediate 8, 540 mg, 86 wt%, 1.09 equiv, 1.32 mmol), 1,10-phenanthroline (87.5 mg, 0.4 equiv, 485 μmol), and potassium carbonate (335 mg, 2 equiv, 2.43 mmol) in DMF (6.00 mL) was sparged with N for 5-10 min, followed by the addition of copper(I) iodide (46.2 mg, 0.2 equiv, 243 μmol) and an additional sparge with N for 5-10 min. The reaction was stirred at 100 °C overnight and then allowed to cool to rt. The reaction mixture was partitioned between DCM (20 mL) and water (10 mL). The organics were further washed with semi-concentrated brine (20 mL × 2), filtered through a phase separator, and concentrated under reduced pressure to give a crude dark green oil (964 mg). The crude material was dissolved in DCM (20 mL), concentrated onto silica, and purified by chromatography on silica gel (24 g cartridge, 0–100% (3:1 EtOAc / EtOH) / isohexane) to give 6-((1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazol-4-yl)thio)phthalazin-1(2H)-one (308.6 mg, 0.74 mmol, 97% purity) as an off-white solid. [ka]

[0172] (Process 2) A suspension of 6-((1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazol-4-yl)thio)phthalazin-1(2H)-one (164 mg, 97 wt%, 1.00 equiv, 395 μmol) and cesium carbonate (463 mg, 3.6 equiv, 1.42 mmol) in DMF (2.00 mL) was stirred at 70° C. for 45 min, followed by the addition of a solution of 5-(chloromethyl)-2,3-dihydrofuro[3,2-b]pyridine, HCl (Intermediate 9, 90.0 mg, 92 wt%, 1.02 equiv, 402 μmol) in DMF (1.80 mL). The reaction mixture was stirred at 50° C. for 5 h and then allowed to stand at rt overnight. The reaction mixture was heated at 50° C. for an additional 5 h. The reaction mixture was precipitated with water (15 mL), extracted, and diluted with EtOAc (30 mL × 3). The combined organics were washed with semi-concentrated brine (50 mL × 3), dried over MgSO, filtered, and concentrated under reduced pressure to give a yellow oil (204 mg). The crude was dissolved in DCM (10 mL), concentrated onto silica, and purified by chromatography on silica gel (12 g cartridge, 0–50% (3:1, EtOAc / EtOH) / isohexane) to give 6-((1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazol-4-yl)thio)-2-((2,3-dihydrofuro[3,2-b]pyridin-5-yl)methyl)phthalazin-1(2H)-one (109.1 mg, 0.20 mmol, 97% purity) as a yellow solid. [ka]

[0173] (Step 3) To a solution of 6-((1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazol-4-yl)thio)-2-((2,3-dihydrofuro[3,2-b]pyridin-5-yl)methyl)phthalazin-1(2H)-one (109 mg, 97 wt%, 1 equiv, 197 μmol) in MeOH (2.00 mL) was added Oxone (243 mg, 2.0 equiv, 395 μmol). The reaction was stirred at rt, then Oxone (24.3 mg, 0.2 equiv, 39.5 μmol) was added and stirred at rt for an additional 3 h. The reaction mixture was diluted with MeOH (15 mL) to give a white solid (359 mg). The crude material was dissolved in DCM (20 mL) and MeOH (3 mL), concentrated onto silica, and purified by chromatography on silica gel (12 g cartridge, 0-5% (0.7 M ammonia / MeOH) / DCM) to give 2-((2,3-dihydrofuro[3,2-b]pyridin-5-yl)methyl)-6-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)sulfonyl)phthalazin-1(2H)-one (41.4 mg, 89 μmol, 98% purity) as a white solid. [ka]

[0174] Example 4: 6-((1H-pyrazol-4-yl)sulfonyl)-2-((2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)methyl)phthalazin-1(2H)-one [ka] (Process 1) To a mixture of 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-thiol (Intermediate 3, 62 g, 337 mmol), 6-bromophthalazin-1(2H)-one (54 g, 241 mmol), CuI (6.4 g, 33.7 mmol), and 1,2,3-benzotriazole (8 g, 67.4 mmol) in NMP (2 L) was added t-BuOK (54 g, 482 mmol) at room temperature. The reaction was stirred overnight at 100° C. under a nitrogen atmosphere. After LCMS showed the reaction was complete, the reaction mixture was added to water (10 L), stirred at room temperature for 3 hours, and filtered. The residue was lyophilized to give 6-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)thio)phthalazin-1(2H)-one (75 g, 98% purity) as a yellow solid. MS(ES+): 329.1(M+H)+.

[0175] (Process 2) To a solution of 6-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)thio)phthalazin-1(2H)-one (328 mg, 1 mmol) and 6-(chloromethyl)-2,3-dihydropyrazolo[5,1-b]oxazole (Intermediate 1, 200 mg, 1.3 mmol) in DMF (10 mL) was added CsCO (652 mg, 2 mmol) at room temperature, and the reaction mixture was stirred at 60 °C for 16 h. After LCMS showed the reaction was complete, water (30 mL) was added to the reaction mixture, and the organics were extracted with EtOAc (20 mL × 3). The combined organic layers were washed with aqueous NHCl, dried over NaSO, filtered, and concentrated under reduced pressure at 45 °C. The residue was purified by flash column chromatography (12 g, dichloromethane / ethyl acetate = 100:0 to 60:40) to give 2-((2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)methyl)-6-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)thio)phthalazin-1(2H)-one (170 mg, 89.77% purity) as a yellow solid. MS(ES+): 451.1 (M+H)+.

[0176] (Step 3) To a solution of 2-((2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)methyl)-6-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)thio)phthalazin-1(2H)-one (170 mg, 0.38 mmol) in DMF (3 mL) was added oxone (700 mg, 1.14 mmol) at room temperature. The reaction was stirred at 60°C for 0.5 h. After LCMS showed the reaction was complete, water (10 ml) was added to the reaction mixture. The mixture was extracted with EtOAc (10 mL x 3). The organic layer was concentrated under reduced pressure at 40°C. The residue was purified by preparative HPLC (column: Waters X-Bridge C18 OBD 10 μm 19 * 250 mm; flow rate: 20 mL / min; solvent system: MeCN / (10 mmol / L NH4HCO3 / water) gradient: MeCN: 38% to 95%; collection wavelength: 214 nm). The relevant fractions were concentrated under reduced pressure at 42 °C to remove MeCN, and the residue was lyophilized to give the title compound (27.87 mg, 100% purity) as a white solid. [ka]

[0177] Example 5: 2-((2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)methyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)phthalazin-1(2H)-one [ka] (Process 1) To a mixture of 1-methyl-1H-pyrazole-4-thiol (Intermediate 10, 27 g, 237 mmol), 6-bromophthalazin-1(2H)-one (38 g, 169 mmol), CuI (3.2 g, 16.9 mmol), and 1,2,3-benzotriazole (4 g, 33.8 mmol) in NMP (1 L) was added t-BuOK (38 g, 338 mmol) at room temperature. The reaction was stirred overnight at 100 °C under a nitrogen atmosphere. After LCMS showed the reaction was complete, the reaction mixture was added to water (10 L), stirred at room temperature for 3 hours, and then filtered. The residue was lyophilized to give 7-((1-methyl-1H-pyrazol-4-yl)thio)phthalazin-1(2H)-one (32.5 g, 100% purity) as a yellow solid. MS(ES+): 259.1(M+H)+.

[0178] (Process 2) To a solution of 7-((1-methyl-1H-pyrazol-4-yl)thio)phthalazin-1(2H)-one (258 mg, 1 mmol) and 6-(chloromethyl)-2,3-dihydropyrazolo[5,1-b]oxazole (Intermediate 1, 200 mg, 1.3 mmol) in DMF (10 mL) was added CsCO (652 mg, 2 mmol) at room temperature, and the reaction mixture was stirred at 60 °C for 16 h. After LCMS showed the reaction was complete, water (30 mL) was added to the reaction mixture, which was extracted with EtOAc (20 mL × 3). The combined organic layers were washed with aqueous NH Cl, dried over Na SO , filtered, and concentrated under reduced pressure at 45 °C. The residue was purified by flash column chromatography (12 g, dichloromethane / ethyl acetate = 100:0 to 60:40) to give 2-((2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)methyl)-6-((1-methyl-1H-pyrazol-4-yl)thio)phthalazin-1(2H)-one (140 mg, 89.77% purity) as a yellow solid. MS(ES+): 381.1 (M+H)+.

[0179] (Step 3) To a mixture of 2-((2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)methyl)-6-((1-methyl-1H-pyrazol-4-yl)thio)phthalazin-1(2H)-one (140 mg, 0.37 mmol) in DMF (3 mL) was added oxone (700 mg, 1.14 mmol) at room temperature. The reaction was stirred at 60° C. for 0.5 h. After LCMS showed the reaction was complete, water (10 ml) was added to the reaction mixture. The mixture was then extracted with EtOAc (10 mL×3). The organic layer was concentrated under reduced pressure at 40° C. The residue was purified by preparative HPLC (column: Waters X-Bridge C18 OBD 10 μm 19 * 250 mm; flow rate: 20 mL / min; solvent system: MeCN / (10 mmol / L NH4HCO3 / water) gradient: MeCN: 38% to 95%; collection wavelength: 214 nm). The relevant fractions were concentrated under reduced pressure at 42 °C to remove MeCN, and the residue was lyophilized to give the title compound (44.63 mg, 100% purity) as a white solid. [ka]

[0180] Example 6: 6-((1H-pyrazol-3-yl)sulfonyl)-2-((4-chloro-5-methyl-1H-pyrazol-3-yl)methyl)phthalazin-1(2H)-one [ka] (Process 1) To a mixture of 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-thiol (Intermediate 4, 2.8 g, 15.2 mmol), 6-bromophthalazin-1(2H)-one (2.9 g, 12.9 mmol), CuI (246 mg, 1.29 mmol), and 1,2,3-benzotriazole (307 mg, 2.58 mmol) in DMF (30 mL) was added t-BuOK (3.4 g, 30.4 mmol) at room temperature. The reaction was stirred overnight at 100° C. under a nitrogen atmosphere. After LCMS showed the reaction was complete, the reaction mixture was added to water (200 mL) and the solid was filtered and dried to give 6-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)thio)phthalazin-1(2H)-one (2.4 g, 72.75% purity) as a yellow solid. MS(ES+): 329.1(M+H)+.

[0181] (Process 2) To a mixture of (4-chloro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methanol (Intermediate 5, 230 mg, 1.0 mmol) in DCM (4 mL) was added SOCl (178 mg, 1.5 mmol). The reaction mixture was stirred at room temperature for 30 minutes. After LCMS analysis showed the reaction was complete, the mixture was concentrated to remove excess SOCl and DCM to give 4-chloro-3-(chloromethyl)-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole as a crude product, which was used in the next step without further purification.

[0182] (Step 3) To a solution of crude 4-chloro-3-(chloromethyl)-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole in DMF (4 mL) was added CsCO (1.95 g, 6.0 mmol) and 6-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)thio)phthalazin-1(2H)-one (328 mg, 1.0 mmol) at room temperature, and the reaction mixture was stirred at room temperature overnight. After LCMS showed the reaction was complete, the reaction mixture was diluted with water (15 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with saturated ammonium chloride solution (40 mL × 2), dried over NaSO, filtered, and concentrated under reduced pressure at 40 °C. The residual solid was purified by flash column chromatography (12 g, petroleum ether / ethyl acetate = 100:00 to 60:30) to give 2-((4-chloro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methyl)-6-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)thio)phthalazin-1(2H)-one (200 mg, 100% purity) as a yellow solid. MS(ES+): 541.2 (M+H)+.

[0183] (Step 4) To a solution of 2-((4-chloro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methyl)-6-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)thio)phthalazin-1(2H)-one (200 mg, 0.37 mmol) in DMF (3 mL) was added oxone (682 mg, 1.11 mmol) and stirred at 60° C. for 1 h. After LCMS showed the reaction was complete, the reaction mixture was diluted with water (5 mL), neutralized with KCO, and extracted with EtOAc (10 mL×4). The organic layer was washed with saturated aqueous NH4Cl (100 mL × 2), concentrated, and purified by flash column chromatography (12 g, dichloromethane / methanol = 100:00 to 95:5) to give 2-((4-chloro-5-methyl-1H-pyrazol-3-yl)methyl)-6-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)sulfonyl)phthalazin-1(2H)-one (180 mg, 81% purity) as a white solid. MS (ES+): 489.2 (M+H)+.

[0184] (Step 5) To a solution of 2-((4-chloro-5-methyl-1H-pyrazol-3-yl)methyl)-6-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)sulfonyl)phthalazin-1(2H)-one (180 mg, 0.37 mol) in DCM (1 mL) was added TFA (3 mL) and the mixture was stirred at room temperature for 1 h. After LCMS showed the reaction was complete, the mixture was concentrated under reduced pressure. The residue was diluted with H2O (15 mL) and the pH was adjusted to 8 with K2CO3. A solid precipitated and the suspension was filtered. The filter cake was purified by preparative HPLC (column: Waters Xbridge Prep C18 OBD 10 μm 19 *250 mm; flow rate: 20 mL / min; solvent system: MeCN / (10 mmol / L NH4HCO3 / water) gradient: MeCN: 25% to 95%; collection wavelength: 214 nm). The fractions were concentrated under reduced pressure at 40° C. to remove MeCN, and the residue was lyophilized to give the title compound (24.64 mg, 100% purity) as a white solid. [ka]

[0185] Biological Example 1 - Human PKM2 Activation Assay Measurement of in vitro activation of recombinant human PKM2 Compound activation of recombinant human PKM2 pyruvate kinase activity was determined by biochemical assay. N-terminal His-tagged hPKM2 was obtained from R&D Systems, and its substrates, phosphoenolpyruvate (PEP) and ADP, were obtained from Sigma-Aldrich and 2B Scientific, respectively. Kinase-Glo® Plus luminescent assay was obtained from Promega. All other reagents were obtained from Sigma-Aldrich. Test compounds were prepared as 10 mM DMSO stocks, and dilution series were prepared in DMSO for direct dilution into assay buffer (pH 7.2) containing 50 mM imidazole, 50 mM KCl, 7 mM MgCl2, 0.01% Tween 20, and 0.05% BSA.

[0186] Assay Procedure Human PKM2 was diluted to a final concentration of 5 pM in assay buffer (pH 7.2) containing 50 mM imidazole, 50 mM KCl, 7 mM MgCl, 0.01% Tween 20, and 0.05% BSA. The enzyme assay buffer mix was dispensed into a 384-well shallow-well white-walled plate (PerkinElmer), and test compounds were added by acoustic dispensing (Echo®, Labcyte). After a 10-minute incubation at room temperature, the enzyme reaction was initiated by acoustic dispensing of ADP+PEP substrate to a final concentration of 254 μM ADP and 53 μM ADP.

[0187] After 60 minutes of incubation on an orbital shaker (300 rpm, 26°C), enzyme activity was quantified by luminescent detection of the generated ATP. Kinase-Glo® Plus reagent was added to each well, and the plate was incubated in the dark on an orbital shaker (300 rpm, 26°C) for an additional 15 minutes, after which luminescence was measured using a plate reader (PHERAstar® FSX, BMG Labtech).

[0188] Percentage of activation was calculated by normalizing the fluorescent signal to the LOW (DMSO vehicle) and HIGH (5 μM TEPP-46) controls on the plate. EC 50 value and E max Values ​​were determined from a 4-parameter logistic fit of the compound concentration-response curves.

[0189] Compounds of formula (Ia) were tested and the results are shown in Table 1 below. Table 1-PKM2 EC 50 Value (μM) and E max value(%) [Table 3] * shows data from replicate experiments.

[0190] Examples 1-6 were tested in this assay and showed lower EC 50 value and / or higher E max As shown by the values, it exhibited improved PKM2 modulating activity compared to mitapivat.

[0191] Biological Example 2 - Human PKLR Activation Assay Measurement of in vitro activation of recombinant human PKLR Compound activation of recombinant human PKLR pyruvate kinase activity was determined by biochemical assay. The N-terminal His-tagged enzyme was obtained from R&D Systems, and its substrates, phosphoenolpyruvate (PEP) and ADP, were obtained from Sigma-Aldrich and 2B Scientific, respectively. The Kinase-Glo® Plus luminescent assay was obtained from Promega. All other reagents were obtained from Sigma-Aldrich. Test compounds were prepared as 10 mM DMSO stocks, and dilution series were prepared in DMSO for direct dilution into assay buffer (pH 7.2) containing 50 mM imidazole, 50 mM KCl, 7 mM MgCl2, 0.01% Tween 20, and 0.05% BSA.

[0192] Assay Procedure Human PKLR was diluted in assay buffer to a final concentration of 5 pM. The enzyme assay buffer mix was dispensed into a 384-well shallow-well white-walled plate, and test compounds were added by acoustic dispensing (Echo®, Labcyte). After a 10-minute incubation at room temperature, the enzyme reaction was initiated by acoustic dispensing of ADP+PEP substrate to a final concentration of 254 μM ADP and 53 μM ADP.

[0193] After 60 minutes of incubation on an orbital shaker (300 rpm, 26°C), enzyme activity was quantified by luminescent detection of the generated ATP. Kinase-Glo® Plus reagent was added to each well, and the plate was incubated in the dark on an orbital shaker (300 rpm, 26°C) for an additional 15 minutes, after which luminescence was measured using a plate reader (PHERAstar® FSX, BMG Labtech).

[0194] Percentage of activation was calculated by normalizing the fluorescent signal to the LOW (DMSO vehicle) and HIGH (5 μM TEPP-46) controls on the plate. EC 50 value and E max Values ​​were determined from a 4-parameter logistic fit of the compound concentration-response curves.

[0195] Several example compounds of formula (Ia) were tested and the results are shown in Table 2 below. Table 2-PKLR EC 50 Value (μM) and E max value(%) [Table 4] * shows data from replicate experiments.

[0196] Examples 1-5 were tested in this assay and showed lower EC 50 value and / or higher E max As shown by the values, it exhibited improved PKLR-modulating activity compared to mitapivat.

[0197] Biological Example 3 - CD4+ T Cell Pyruvate Kinase Assay Measurement of pyruvate kinase (PK) activity in human CD4+ T cell lysates PKM2 activators increase the pyruvate kinase activity of both recombinant human PKM2 protein and PKM2 in human cell lysates (Kung et al., 2012). Compound activation of pyruvate kinase in human CD4+ T cell lysates was determined by biochemical assay. To improve the disease relevance of the assay, primary CD4+ T cells were used rather than cancer cell lines. PK assays were obtained from Abcam. All other reagents were obtained from ThermoFisher. Test compounds were prepared as 10 mM DMSO stocks, and dilution series were prepared in DMSO for addition to intact CD4+ T cells cultured in RPMI medium containing 10% FBS.

[0198] Assay Procedure Human CD4+ T cells were incubated with compounds for 20 minutes, then washed twice in 1x PBS and resuspended in Abcam PK lysis buffer to prepare cell lysates. 10 μl of PK assay reaction mix containing an OXIRED™ probe was added per well. Plates were read at OD570nm in kinetic mode for 48 minutes (25 cycles of 2 minutes) at 25°C in the dark using a BMG Labtech Pherastar plate reader.

[0199] (Data Analysis) Plates were blank subtracted and the delta absorbance was calculated by subtracting the first plate reading within the linear range from the plate read at the desired time point. PK activity is expressed as delta absorbance and plotted against log[compound].

[0200] Examples 1 to 6 were tested. The results are shown in Table 3 below. Mitapivat was tested as a comparative compound. Table 3 - CD4+ T cell pyruvate kinase activity [Table 5]

[0201] Examples 1-6 were tested in this assay and their EC values ​​compared to mitapivat were 50 As shown by the values, the α-glucanase activity was improved.

[0202] (References) [Table 6]

[0203] (others) All references mentioned in this application, including patents and patent applications, are incorporated herein by reference to the fullest extent possible.

[0204] Unless the context requires otherwise, throughout this specification and the claims that follow, the word "comprise", and variations such as "comprises" and "comprising", are understood to mean the inclusion of a stated integer, step, group of integers, or group of steps, but not the exclusion of any other integer, step, group of integers, or group of steps.

[0205] This application of which the specification and claims form part may be used as a basis for priority in respect of any subsequent application. The claims of such subsequent application may be directed to any feature or combination of features described herein. They may take the form of product, composition, process, or use claims and may include, by way of example and without limitation, the following claims:

Claims

1. Compounds of formula (Ia): 【Chemistry 1】 (In the formula: (a)R A is pyrazolyl and R B is pyridinyl substituted with one OMe group, and 6-((1H-pyrazol-4-yl)sulfonyl)-2-((5-methoxypyridin-2-yl)methyl)phthalazin-1(2H)-one 【Chemistry 2】 Will it result in; (b)R A is CHF 2 pyrazolyl substituted by R B is pyrazolyl and 2-((1H-pyrazol-3-yl)methyl)-6-((1-(difluoromethyl)-1H-pyrazol-4-yl)sulfonyl)phthalazin-1(2H)-one 【Transformation 3】 Will it result in; (c)R A is CH 2 CH 2 pyrazolyl substituted by OH, R B is dihydrofuro[3,2-b]pyridinyl, 2-((2,3-dihydrofuro[3,2-b]pyridin-5-yl)methyl)-6-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)sulfonyl)phthalazin-1(2H)-one 【Chemistry 4】 Will it result in; (d)R A is pyrazolyl and R B is 2,3-dihydropyrazolo[5,1-b]oxazolyl and 6-((1H-pyrazol-4-yl)sulfonyl)-2-((2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)methyl)phthalazin-1(2H)-one 【Transformation 5】 Will it result in; (e)R A is pyrazolyl substituted by methyl, and R B is 2,3-dihydropyrazolo[5,1-b]oxazolyl, 2-((2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)methyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)phthalazin-1(2H)-one 【Transformation 6】 or (f)R A is pyrazolyl and R B is a pyrazolyl substituted with one Cl and one methyl, and is 6-((1H-pyrazol-3-yl)sulfonyl)-2-((4-chloro-5-methyl-1H-pyrazol-3-yl)methyl)phthalazin-1(2H)-one 【Transformation 7】 (resulting in or a salt and / or solvate thereof.

2. 6-((1H-pyrazol-4-yl)sulfonyl)-2-((5-methoxypyridin-2-yl)methyl)phthalazin-1(2H)-one 【Transformation 8】 2. A compound of formula (Ia) or a salt and / or solvate thereof according to claim 1, wherein the compound is:

3. 6-((1H-pyrazol-4-yl)sulfonyl)-2-((5-methoxypyridin-2-yl)methyl)phthalazin-1(2H)-one 【Chemistry 9】 3. The compound of formula (Ia) according to claim 2, wherein:

4. 6-((1H-pyrazol-4-yl)sulfonyl)-2-((5-methoxypyridin-2-yl)methyl)phthalazin-1(2H)-one 【Chemistry 10】 3. A compound of formula (Ia) or a salt and / or solvate thereof according to claim 2, which is a salt thereof, for example a pharmaceutically acceptable salt.

5. 2-((1H-pyrazol-3-yl)methyl)-6-((1-(difluoromethyl)-1H-pyrazol-4-yl)sulfonyl)phthalazin-1(2H)-one 【Chemistry 11】 2. A compound of formula (Ia) or a salt and / or solvate thereof according to claim 1, wherein the compound is:

6. 2-((1H-pyrazol-3-yl)methyl)-6-((1-(difluoromethyl)-1H-pyrazol-4-yl)sulfonyl)phthalazin-1(2H)-one 【Chemistry 12】 6. The compound of formula (Ia) according to claim 5, wherein:

7. 2-((1H-pyrazol-3-yl)methyl)-6-((1-(difluoromethyl)-1H-pyrazol-4-yl)sulfonyl)phthalazin-1(2H)-one 【Chemistry 13】 6. A compound of formula (Ia) or a salt and / or solvate thereof according to claim 5, which is a salt thereof, for example a pharmaceutically acceptable salt.

8. 2-((2,3-Dihydrofuro[3,2-b]pyridin-5-yl)methyl)-6-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)sulfonyl)phthalazin-1(2H)-one 【Chemistry 14】 2. A compound of formula (Ia) or a salt and / or solvate thereof according to claim 1, wherein the compound is:

9. 2-((2,3-Dihydrofuro[3,2-b]pyridin-5-yl)methyl)-6-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)sulfonyl)phthalazin-1(2H)-one 【Chemistry 15】 9. The compound of formula (Ia) according to claim 8, wherein:

10. 2-((2,3-Dihydrofuro[3,2-b]pyridin-5-yl)methyl)-6-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)sulfonyl)phthalazin-1(2H)-one 【Chemistry 16】 9. A compound of formula (Ia) or a salt and / or solvate thereof according to claim 8, which is a salt thereof, for example a pharmaceutically acceptable salt.

11. 6-((1H-pyrazol-4-yl)sulfonyl)-2-((2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)methyl)phthalazin-1(2H)-one 【Chemistry 17】 2. A compound of formula (Ia) or a salt and / or solvate thereof according to claim 1, wherein the compound is:

12. 6-((1H-pyrazol-4-yl)sulfonyl)-2-((2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)methyl)phthalazin-1(2H)-one [Chemistry 18] 12. The compound of formula (Ia) according to claim 11, wherein:

13. 6-((1H-pyrazol-4-yl)sulfonyl)-2-((2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)methyl)phthalazin-1(2H)-one 【Chemistry 19】 12. A compound of formula (Ia) or a salt and / or solvate thereof according to claim 11, which is a salt of, for example a pharmaceutically acceptable salt.

14. 2-((2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)methyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)phthalazin-1(2H)-one 【Chemistry 20】 2. The compound of formula (Ia) according to claim 1, or a salt and / or solvate thereof.

15. 2-((2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)methyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)phthalazin-1(2H)-one 【Chemistry 21】 15. The compound of formula (Ia) according to claim 14, wherein:

16. 2-((2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)methyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)phthalazin-1(2H)-one 【Chemistry 22】 15. A compound of formula (Ia) or a salt and / or solvate thereof according to claim 14, which is a salt thereof, for example a pharmaceutically acceptable salt.

17. 6-((1H-pyrazol-3-yl)sulfonyl)-2-((4-chloro-5-methyl-1H-pyrazol-3-yl)methyl)phthalazin-1(2H)-one 【Chemistry 23】 2. A compound of formula (Ia) or a salt and / or solvate thereof according to claim 1, wherein the compound is:

18. 6-((1H-pyrazol-3-yl)sulfonyl)-2-((4-chloro-5-methyl-1H-pyrazol-3-yl)methyl)phthalazin-1(2H)-one 【Chemistry 24】 18. The compound of formula (Ia) according to claim 17, wherein:

19. 6-((1H-pyrazol-3-yl)sulfonyl)-2-((4-chloro-5-methyl-1H-pyrazol-3-yl)methyl)phthalazin-1(2H)-one 【Chemistry 25】 18. A compound of formula (Ia) or a salt and / or solvate thereof according to claim 17, which is a salt thereof, for example a pharmaceutically acceptable salt.

20. 20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt and / or solvate thereof and one or more pharmaceutically acceptable diluents or carriers.

21. A compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt and / or solvate thereof or a pharmaceutical composition according to claim 20 for use as a medicament.

22. A compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt and / or solvate thereof or a pharmaceutical composition according to claim 20 for use in the treatment or prevention of a disease, disorder or condition associated with the function of PK, in particular PKM2 and / or PKLR.

23. Use of a compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt and / or solvate thereof or a pharmaceutical composition according to claim 20 in the manufacture of a medicament for treating or preventing a disease, disorder or condition associated with the function of PK, in particular PKM2 and / or PKLR.

24. A method for treating or preventing a disease, disorder, or condition associated with the function of PK, in particular PKM2 and / or PKLR, said method comprising administering a compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt and / or solvate thereof, or a pharmaceutical composition according to claim 20.

25. 25. A compound for use, or a pharmaceutically acceptable salt and / or solvate thereof, pharmaceutical composition for use, use, or method according to any one of claims 22 to 24, for treating or preventing an inflammatory disease, a disease associated with an unwanted immune response, cancer, obesity, a diabetic disease, or a blood disorder.

26. 26. A compound for use, or a pharmaceutically acceptable salt and / or solvate thereof, pharmaceutical composition for use, use, or method according to claim 25, for treating an inflammatory disease or a disease associated with an undesired immune response.

27. 26. A compound for use, or a pharmaceutically acceptable salt and / or solvate thereof, pharmaceutical composition for use, use, or method according to claim 25, for preventing an inflammatory disease or a disease associated with an undesired immune response.

28. 26. A compound for use, or a pharmaceutically acceptable salt and / or solvate thereof, pharmaceutical composition for use, use, or method according to claim 25, for treating or preventing an inflammatory disease.

29. 26. A compound for use, or a pharmaceutically acceptable salt and / or solvate thereof, pharmaceutical composition for use, use, or method according to claim 25, for treating or preventing a disease associated with an undesired immune response.

30. 26. The compound for use or a pharmaceutically acceptable salt and / or solvate thereof, pharmaceutical composition for use, use, or method according to claim 25, wherein the inflammatory disease or disease associated with an undesired immune response is selected from the group consisting of Crohn's disease, ulcerative colitis, type 2 diabetes, atopic dermatitis, hidradenitis suppurativa, psoriasis, bullous pemphigoid, pemphigus vulgaris, localized and diffuse scleroderma, Sjogren's syndrome, polymyositis, dermatomyositis, Behcet's disease, wound healing, rheumatoid arthritis, systemic lupus erythematosus, cutaneous lupus erythematosus, graft versus host disease, multiple sclerosis, organ fibrosis (including liver, lung, kidney), COPD, and asthma.

31. 26. The compound for use or a pharmaceutically acceptable salt and / or solvate thereof, pharmaceutical composition for use, use, or method according to claim 25, wherein the inflammatory disease or disease associated with an undesired immune response is selected from the group consisting of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, systemic lupus erythematosus, multiple sclerosis, psoriasis, inflammatory bowel disease (including ulcerative colitis and Crohn's disease), atopic dermatitis, fibrosis, uveitis, cryopyrin-associated periodic syndrome, Muckle-Wells syndrome, juvenile idiopathic arthritis, chronic obstructive pulmonary disease, and asthma.

32. 32. The compound for use, or a pharmaceutically acceptable salt and / or solvate thereof, pharmaceutical composition for use, use, or method according to claim 31, wherein the inflammatory disease or disease associated with an undesired immune response is multiple sclerosis.

33. 32. The compound for use, or a pharmaceutically acceptable salt and / or solvate thereof, pharmaceutical composition for use, use, or method according to claim 31, wherein the inflammatory disease or disease associated with an undesired immune response is psoriasis.

34. 32. The compound for use, or a pharmaceutically acceptable salt and / or solvate thereof, pharmaceutical composition for use, use, or method according to claim 31, wherein the inflammatory disease or disease associated with an undesired immune response is asthma.

35. 32. The compound for use, or a pharmaceutically acceptable salt and / or solvate thereof, pharmaceutical composition for use, use, or method according to claim 31, wherein the inflammatory disease or disease associated with an undesired immune response is chronic obstructive pulmonary disease.

36. 32. The compound for use, or a pharmaceutically acceptable salt and / or solvate thereof, pharmaceutical composition for use, use, or method according to claim 31, wherein the inflammatory disease or disease associated with an unwanted immune response is systemic lupus erythematosus.

37. 32. The compound for use, or a pharmaceutically acceptable salt and / or solvate thereof, pharmaceutical composition for use, use, or method according to claim 31, wherein the inflammatory disease or disease associated with an undesired immune response is rheumatoid arthritis.

38. 32. The compound for use, or a pharmaceutically acceptable salt and / or solvate thereof, pharmaceutical composition for use, use, or method according to claim 31, wherein the inflammatory disease or disease associated with an undesired immune response is inflammatory bowel disease (including ulcerative colitis and Crohn's disease).

39. 32. The compound for use, or a pharmaceutically acceptable salt and / or solvate thereof, pharmaceutical composition for use, use, or method according to claim 31, wherein the inflammatory disease or disease associated with an undesired immune response is atopic dermatitis.

40. 32. The compound for use, or a pharmaceutically acceptable salt and / or solvate thereof, pharmaceutical composition for use, use, or method according to claim 31, wherein the inflammatory disease or disease associated with an undesired immune response is fibrosis.

41. 26. A compound for use according to claim 25, or a pharmaceutically acceptable salt and / or solvate thereof, a pharmaceutical composition for use, a use, or a method for treating cancer.

42. 26. A compound for use according to claim 25, or a pharmaceutically acceptable salt and / or solvate thereof, a pharmaceutical composition for use, a use, or a method for preventing cancer.

43. Cancers include: acute lymphoblastic leukemia, adult; acute lymphoblastic leukemia, pediatric; acute myeloid leukemia, adult; adrenocortical carcinoma; adrenocortical carcinoma, pediatric; AIDS-related lymphoma; AIDS-related malignancies; anal cancer; cerebellar astrocytoma, pediatric; cerebral astrocytoma, pediatric; Barrett's esophagus (premalignant syndrome); extrahepatic bile duct cancer; bladder cancer; pediatric bladder cancer; bone cancer, osteosarcoma / malignant fibrous histiocytoma; pediatric brainstem glioma; brain tumor, adult; brain tumor, brainstem glioma, pediatric; brain tumor, cerebellar astrocytoma, pediatric; brain tumor, cerebral astrocytoma / malignant glioma, pediatric; brain tumor, ependymoma, pediatric; brain tumor, medulloblastoma, pediatric; supratentorial brain tumor Primitive neuroectodermal tumor, pediatric;Brain tumor, optic tract and hypothalamic glioma, pediatric;Brain tumor, pediatric (other);Breast cancer;Breast cancer and pregnancy;Breast cancer, pediatric;Breast cancer, male;Bronchial adenoma / carcinoid, pediatric;Carcinoid tumor, pediatric;Carcinoid tumor, gastrointestinal;Carcinoma, adrenal cortex;Carcinoma, pancreatic islet cell;Carcinoma of unknown primary;Central nervous system lymphoma, primary;Cerebellar astrocytoma, pediatric;Cerebral astrocytoma / malignant glioma, pediatric;Cervical cancer;Pediatric cancer;Chronic lymphocytic leukemia;Chronic myelogenous leukemia;Chronic myeloproliferative disorder;Clear cell sarcoma of tendon sheath;Colon cancer;Colorectal cancer;Colorectal cancer, pediatric;Cutaneous T-cell lymphoma;Endometrial Cancer; Ependymoma, pediatric; Epithelial carcinoma, ovarian; Esophageal cancer; Esophageal cancer, pediatric; Ewing family tumors; Extracranial germ cell tumors, pediatric; Extragonadal germ cell tumors; Extrahepatic bile duct cancer; Eye cancer, intraocular melanoma; Eye cancer, retinoblastoma; Gallbladder cancer; Gastric cancer; Gastric cancer, pediatric; Gastrointestinal carcinoid tumors; Germ cell tumors, extracranial, pediatric; Germ cell tumors, extragonadal; Germ cell tumors, ovarian; Gestational trophoblastic tumors; Glioma, pediatric brainstem; Glioma, pediatric visual pathway and hypothalamic; Hairy cell leukemia; Head and neck cancer; Hepatocellular (liver) carcinoma; Hepatocellular (liver) carcinoma, adult (primary); Hepatocellular (liver) carcinoma, pediatric (primary); Cancer of the esophagus; Hodgkin's lymphoma ;Hodgkin's lymphoma, adult;Hodgkin's lymphoma, childhood;Hodgkin's lymphoma, pregnancy;Hypopharyngeal cancer;Hypothalamic and optic tract glioma, childhood;Intraocular melanoma;Islet cell carcinoma (endocrine pancreas);Cancer of the endocrine system (e.g., cancer of the thyroid, pancreas, parathyroid, or adrenal gland);Kaposi's sarcoma;Kidney cancer;Laryngeal cancer;Laryngeal cancer, childhood;Leukemia, acute lymphoblastic, adult;Leukemia, acute lymphoblastic, childhood;Leukemia, acute myeloid, adult;Leukemia, acute myeloid, childhood;Leukemia, chronic lymphocytic;Leukemia, chronic myeloid;Leukemia, hairy cell;Lymphocytic lymphoma;Lip and oral cavity cancer;Liver cancer, adult (primary);Liver cancer, childhood (primary); Lung cancer; Lung cancer, non-small cell; Lung cancer, small cell; Lymphoblastic leukemia, adult acute; Lymphoblastic leukemia, childhood acute; Lymphocytic leukemia, chronic; Lymphoma, AIDS-related; Lymphoma, central nervous system (primary); Lymphoma, cutaneous T-cell; Lymphoma, Hodgkin, adult; Lymphoma, Hodgkin, childhood; Lymphoma, Hodgkin, pregnancy; Lymphoma, non-Hodgkin, adult; Lymphoma, non-Hodgkin, childhood; Lymphoma, non-Hodgkin, pregnancy; Lymphoma, central nervous system primary; Macroglobulinemia, Waldenstrom; Male breast cancer; Malignant mesothelioma, adult; Malignant mesothelioma Pediatric tumors; Malignant thymoma; Medulloblastoma, childhood; Melanoma; Melanoma, intraocular; Merkel cell carcinoma; Mesothelioma, malignant; Metastatic squamous cell carcinoma of the neck with unknown primary; Multiple endocrine neoplasia syndrome, childhood; Multiple myeloma / plasma cell neoplasm; Mycosis fungoides; Myelodysplastic syndrome; Myeloid leukemia, chronic; Myeloid leukemia, acute, childhood; Myeloma, multiple; Myeloproliferative disorders, chronic; Cancer of the nasal cavity and paranasal sinuses; Nasopharyngeal carcinoma; Nasopharyngeal carcinoma, childhood; Neoplastic skin diseases; Neuroblastoma; Non-Hodgkin's lymphoma, adult; Non-Hodgkin's lymphoma, childhood; Non-Hodgkin's lymphoma, pregnancy; Non-small cell lung carcinoma; Neoplasms of the central nervous system (e.g., primary C) NS lymphoma, spinal axis tumor, medulloblastoma, brainstem glioma, or pituitary adenoma); oat cell carcinoma; oral cavity cancer, pediatric; oral cavity and lip cancer; oropharyngeal cancer; osteosarcoma / malignant fibrous histiocytoma of bone; ovarian cancer; ovarian cancer, pediatric; ovarian epithelial cancer; ovarian germ cell tumor; ovarian low malignant potential tumor; pediatric malignancies; pancreatic cancer; pancreatic cancer, pediatric; pancreatic islet cell cancer; paranasal sinus and nasal cancer; parathyroid carcinoma; penile cancer; pheochromocytoma; pineal and supratentorial primitive neuroectodermal tumor, pediatric; pituitary tumor; plasma cell neoplasm / multiple myeloma; pleuropulmonary blastoma; pregnancy and breast cancer; pregnancy and Hodgkin's lymphoma; pregnancy and non-Hodgkin's lymphoma; primary pulmonary Central nervous system lymphoma; Primary liver cancer, adult; Primary liver cancer, pediatric; Prostate cancer (especially hormone-refractory); Chronic or acute leukemia; Solid tumors of childhood; Hypereosinophilia; Rectal cancer; Renal cell (kidney) cancer; Renal cell carcinoma, pediatric; Renal pelvis and ureter, transitional cell carcinoma; Retinoblastoma; Rhabdomyosarcoma, pediatric; Salivary gland cancer; Salivary gland cancer, pediatric; Sarcoma, Ewing's family of tumors; Sarcoma, Kaposi's; Sarcoma (osteosarcoma) / malignant fibrous histiocytoma of bone; Sarcoma, rhabdomyosarcoma, pediatric; Sarcoma of soft tissue; Sarcoma, soft tissue, adult; Sarcoma, soft tissue, pediatric; Sezary syndrome; Skin cancer; Skin cancer, pediatric; Skin cancer (melanoma);Skin cancer, Merkel cell;Small cell lung cancer;Dermatofibrosarcoma protuberans;Small intestinal cancer;Soft tissue sarcoma, adult;Soft tissue sarcoma, pediatric;Head and neck cancer;Squamous cell neck carcinoma of unknown primary, metastatic;Gastric cancer;Gastric cancer, pediatric;Supratentorial primitive neuroectodermal tumor, pediatric; 43. The compound or pharmaceutically acceptable salt and / or solvate thereof for use according to claim 41 or 42, selected from the group consisting of T-cell lymphoma, skin; testicular cancer; thymoma, pediatric; thymoma, malignant; thyroid cancer; thyroid cancer, pediatric; transitional cell carcinoma of the renal pelvis and ureter; trophoblastic tumor, gestational; pediatric cancer of unknown primary site; rare cancers of childhood; ureter and renal pelvis, transitional cell carcinoma; urethral cancer; cancer of the ureter (e.g., renal cell carcinoma, renal pelvis cancer); cancer of the penis; gynecological tumors; uterine cancer; uterine sarcoma; cancer of the fallopian tube; cancer of the endometrium; vaginal cancer; cancer of the vagina; cancer of the vulva; optic tract and hypothalamic glioma, pediatric; vulvar cancer; Waldenstrom's macroglobulinemia; and Wilms' tumor, or a pharmaceutically acceptable salt and / or solvate thereof for use, pharmaceutical composition for use, use, or method.

44. Cancers include lung cancer; NSCLC (non-small cell lung cancer); oat cell carcinoma; bone cancer; pancreatic cancer; skin cancer; dermatofibrosarcoma protuberans; cancer of the head and neck; cutaneous or intraocular melanoma; uterine cancer; ovarian cancer; colorectal cancer; anal cancer; stomach cancer; colon cancer; breast cancer; gynecological tumors (e.g., uterine sarcoma, cancer of the fallopian tubes, endometrial cancer, cervical cancer, vaginal cancer, or vulvar cancer); Hodgkin's disease; hepatocellular carcinoma; cancer of the esophagus; small intestine cancer; cancer of the endocrine system (e.g., cancer of the thyroid, pancreas, parathyroid, or adrenal gland); soft tissue sarcoma; urethral cancer; penile cancer; and prostate cancer (especially hormone-refractory).

44. The compound or its pharmaceutically acceptable salt and / or solvate for use, pharmaceutical composition for use, use, or method according to claim 43, selected from the group consisting of: chronic or acute leukemia; pediatric solid tumors; hypereosinophilia; lymphocytic lymphoma; bladder cancer; kidney cancer; cancer of the urinary tract (e.g., renal cell carcinoma, carcinoma of the renal pelvis); pediatric malignant tumors; neoplasms of the central nervous system (e.g., primary CNS lymphoma, spinal axis tumor, medulloblastoma, brainstem glioma, or pituitary adenoma); Barrett's esophagus (premalignant syndrome), and neoplastic skin diseases.

45. 26. A compound for use, or a pharmaceutically acceptable salt and / or solvate thereof, pharmaceutical composition for use, use, or method according to claim 25, for treating obesity.

46. 26. A compound for use according to claim 25, or a pharmaceutically acceptable salt and / or solvate thereof, a pharmaceutical composition for use, a use, or a method for preventing obesity.

47. 26. A compound for use, or a pharmaceutically acceptable salt and / or solvate thereof, pharmaceutical composition for use, use, or method according to claim 25, for treating a diabetic disease.

48. 26. A compound for use according to claim 25, or a pharmaceutically acceptable salt and / or solvate thereof, a pharmaceutical composition for use, a use, or a method for preventing a diabetic disease.

49. 49. The compound for use, or a pharmaceutically acceptable salt and / or solvate thereof, pharmaceutical composition for use, use, or method according to claim 47 or 48, wherein the diabetic disease is selected from diabetes and diabetic complications.

50. 50. The compound for use, or a pharmaceutically acceptable salt and / or solvate thereof, pharmaceutical composition for use, use, or method according to claim 49, wherein the diabetes is type 1 diabetes.

51. 50. The compound for use, or a pharmaceutically acceptable salt and / or solvate thereof, pharmaceutical composition for use, use, or method according to claim 49, wherein the diabetes is type 2 diabetes.

52. 50. The compound for use, or a pharmaceutically acceptable salt and / or solvate thereof, pharmaceutical composition for use, use, or method according to claim 49, wherein the diabetic complication is selected from the group consisting of coronary artery disease, peripheral artery disease, stroke, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic kidney disease, and NASH.

53. 26. A compound for use, or a pharmaceutically acceptable salt and / or solvate thereof, pharmaceutical composition for use, use, or method according to claim 25, for treating a blood disorder.

54. 26. A compound for use, or a pharmaceutically acceptable salt and / or solvate thereof, pharmaceutical composition for use, use, or method according to claim 25, for preventing blood disorders.

55. 55. The compound for use or a pharmaceutically acceptable salt and / or solvate thereof, pharmaceutical composition for use, use, or method according to claim 53 or 54, wherein the blood disorder is selected from the group consisting of thalassemia (e.g., beta-thalassemia), hereditary spherocytosis, hereditary elliptocytosis, abetalipoproteinemia (or Bassen-Kornzweig syndrome), paroxysmal nocturnal hemoglobinuria, acquired hemolytic anemia (e.g., congenital anemia (e.g., enzymopathy)), anemia of chronic disease, pyruvate kinase deficiency (PKD), and sickle cell disease.

56. 56. The compound for use, or a pharmaceutically acceptable salt and / or solvate thereof, pharmaceutical composition for use, use, or method according to any one of claims 21 to 55, wherein said compound is for administration to a human subject.

57. 57. A compound for use, or a pharmaceutically acceptable salt and / or solvate thereof, pharmaceutical composition for use, use, or method according to any one of claims 21 to 56, for use in combination with a further therapeutic agent.

58. Corticosteroids (glucocorticoids), retinoids (e.g., acitretin, isotretinoin, tazarotene), anthralin, vitamin D analogs (e.g., cacitriol, calcipotriol), calcineurin inhibitors (e.g., tacrolimus, pimecrolimus), phototherapy or photochemotherapy (e.g., psoralen ultraviolet radiation, PUVA) or other forms of ultraviolet radiation therapy, cyclosporine, thiopurines (e.g., azathioprine, 6-mercaptopurine), methotrexate, anti-TNFα agents (e.g., infliximab, etanercept, adalimumab , certolizumab, golimumab, or biosimilars), phosphodiesterase-4 (PDE4) inhibitors (e.g., apremilast, crisaborole), anti-IL-17 agents (e.g., brodalumab, ixekizumab, secukinumab), anti-IL-12 / IL-23 agents (e.g., ustekinumab, briakinumab), anti-IL-23 agents (e.g., guselkumab, tildrakizumab), JAK (Janus kinase) inhibitors (e.g., tofacitinib, ruxolitinib, baricitinib, filgotinib, upadacitinib), plasma exchange, intravenous immunoglobulin (IVIG), cyclophosphamide, anti-CD20 B-cell depleting agents (e.g., rituximab, ocrelizumab, ofatumumab, obinutuzumab), anthracycline analogs (e.g., mitoxantrone), cladribine, sphingosine 1-phosphate receptor modulators or sphingosine analogs (e.g., fingolimod, siponimod, ozanimod, etrasimod), interferon beta preparations (including interferon beta 1b / 1a), glatiramer, anti-CD3 therapy (e.g., OKT3), anti-CD52 targeted agents (e.g., alemtuzumab), leflunomide, teriflunomide, gold compounds, laquinimod, potassium channel blockers (e.g., dalfampicin, benzodiazepine / 4-aminopyridine), mycophenolic acid, mycophenolate mofetil, purine analogs (e.g., pentostatin), mTOR (target of rapamycin) pathway inhibitors (e.g., sirolimus, everolimus), antithymocyte globulin (ATG), IL-2 receptor (CD25) inhibitors (e.g., basiliximab, daclizumab), anti-IL-6 receptor or anti-IL-6 agents (e.g., tocilizumab, siltuximab),Other B-cell targeted therapies, including Bruton's tyrosine kinase (BTK) inhibitors (e.g., ibrutinib), tyrosine kinase inhibitors (e.g., imatinib), ursodeoxycholic acid, hydroxychloroquine, chloroquine, B-cell activating factor (BAFF, also known as BlyS, B-lymphocyte stimulatory factor) inhibitors (e.g., belimumab, blissibimod), fusion proteins targeting both APRIL (proliferative inducing ligand) and BlyS (e.g., atacicept), pan-inhibitors or PI3 inhibitors, including those targeting p110δ- and / or p110γ-containing isoforms K inhibitors (e.g., idelalisib, copanlisib, duvelisib), interferon α receptor inhibitors (e.g., anifrolumab, sifalimumab), T cell costimulation blockers (e.g., abatacept, belatacept), thalidomide and its derivatives (e.g., lenalidomide), dapsone, clofazimine, leukotriene antagonists (e.g., montelukast), theophylline, anti-IgE therapy (e.g., omalizumab), anti-IL-5 agents (e.g., mepolizumab, reslizumab), long-acting muscarinic agents (e.g., tiotropium, aclidinium, ium, umeclidinium), PDE4 inhibitors (e.g., roflumilast), riluzole, free radical scavengers (e.g., edaravone), proteasome inhibitors (e.g., bortezomib), complement cascade inhibitors including those directed against C5 (e.g., eculizumab), immunoadsorbents, antithymocyte globulin, 5-aminosalicylates and their derivatives (e.g., sulfasalazine, balsalazide, mesalamine), antiintegrin agents including those targeting α4β1 and / or α4β7 integrins (e.g., natalizumab, vedolizumab). , anti-CD11-α agents (e.g., efalizumab), nonsteroidal anti-inflammatory drugs (NSAIDs) including salicylates (e.g., aspirin), propionic acids (e.g., ibuprofen, naproxen), acetates (e.g., indomethacin, diclofenac, etodolac), oxicams (e.g., meloxicam), and fenamates (e.g., mefenamic acid), selective or relatively selective COX-2 inhibitors (e.g., celecoxib, etroxicoxib, valdecoxib, etodolac, meloxicam, nabumetone), colchicine,IL-4 receptor inhibitors (e.g., dupilumab), topical / contact immunotherapy (e.g., diphenylcyclopropenone, squaric acid dibutyl ester), anti-IL-1 receptor therapy (e.g., anakinra), IL-1β inhibitors (e.g., canakinumab), IL-1 neutralizing therapy (e.g., rilonacept), chlorambucil, certain antibiotics with immunomodulatory properties and / or the ability to modulate NRF2 (e.g., minocycline, tetracyclines including clindamycin, macrolide antibiotics), antiandrogen therapy (e.g., cyproterone, spironolactone, The compound for use or a pharmaceutically acceptable salt and / or solvate thereof, pharmaceutical composition for use, use, or method according to any one of claims 26 to 40, for use in combination with an additional therapeutic agent selected from the group consisting of finasteride, pentoxifylline, ursodeoxycholic acid, obeticholic acid, fibrates, cystic fibrosis transmembrane conductance regulator (CFTR) modulators, VEGF (vascular endothelial growth factor) inhibitors (e.g., bevacizumab, ranibizumab, pegaptanib, aflibercept), pirfenidone, or mizoribine.

59. 45. The compound for use or a pharmaceutically acceptable salt and / or solvate thereof, pharmaceutical composition for use, use, or method according to any one of claims 41 to 44, for use in combination with a further therapeutic agent selected from the group consisting of palliative treatments such as those selected from the group consisting of: antiemetics, drugs intended to relieve pain such as opioids, drugs used to lower high blood uric acid levels such as allopurinol or rasburicase, antidepressants, sedatives, anticonvulsants, laxatives, antidiarrheals, and / or antacids.

60. 45. The compound for use, or a pharmaceutically acceptable salt and / or solvate thereof, pharmaceutical composition for use, use, or method according to any one of claims 41 to 44, for use in combination with an additional cancer treatment selected from the group consisting of chemotherapy, targeted therapy, immunotherapy, and hormonal therapy.

61. The chemotherapeutic agent is selected from the group consisting of aclarubicin, actinomycin, alitretinone, altretamine, aminopterin, aminolevulinic acid, amrubicin, amsacrine, anagrelide, arsenic trioxide, asparaginase, atrasentan, belotecan, bexarotene, endamustine, bleomycin, bortezomib, busulfan, camptothecin, capecitabine, carboplatin, carboquone, carmofur, carmustine, celecoxib, chlorambucil, chlormethine, cisplatin, cladribine, clofarabine, crisantaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, decitabine, demecolcine, docetaxel, doxorubicin, efaproxiral, elesclomol, elsamitrucin, enocitabine, epirubicin, estramustine, etoglucide, etoposide, floxuridine, fludarabine, fluorouracil (5FU), fotemustine, gemcitabine, gliadel implant, hydroxycarbamide, hydroxyurea, idarubicin, ifosfamide, irinotecan , irofulven, ixabepilone, larotaxel, leucovorin, liposomal doxorubicin, liposomal daunorubicin, lonidamine, lomustine, lucanthone, mannosulfan, masoprocol, melphalan, mercaptopurine, mesna, methotrexate, methyl aminolevulinate, mitobronitol, mitoguazone, mitotane, mitomycin, mitoxantrone, nedaplatin, nimustine, oblimersen, omacetaxine, ortataxel, oxaliplatin, paclitaxel, pegaspargase, pemetrexed, pentostatin , pirarubicin, pixantrone, plicamycin, porfimer sodium, prednimustine, procarbazine, raltitrexed, ranimustine, rubitecan, sapacitabine, semustine, sitimagene seradenovec, satraplatin, streptozocin, talaporfin, tegafur-uracil, temoporfin, temozolomide, teniposide, tesetaxel, testolactone, tetranitrate, thiotepa, tiazofurin, thioguanine, tipifarnib, topotecan, trabectedin, triaziconazole, triethylenemelamine, triplatin,61. The compound for use according to claim 60, or a pharmaceutically acceptable salt and / or solvate thereof, pharmaceutical composition for use, use, or method, selected from the group consisting of tretinoin, treosulfan, trofosfamide, uramustine, valrubicin, verteporfin, vinblastine, vincristine, vindesine, vinfhmine, vinorelbine, vorinostat, and zorubicin.

62. 61. The compound or a pharmaceutically acceptable salt and / or solvate thereof for use, pharmaceutical composition for use, use, or method according to claim 60, wherein the targeted therapy is selected from the group consisting of axitinib, bosutinib, cediranib, dasatinib, erlotinib, imatinib, gefitinib, lapatinib, lestaurtinib, nilotinib, semaxanib, sorafenib, sunitinib, vandetanib, alvocidib, seliciclib, herceptin, rituximab, tositumomab, cetuximab, panitumumab, trastuzumab, alemtuzumab, bevacizumab, edrecolomab, gemtuzumab, aflibercept, denileukin diftitox, and bexar.

63. Gastric or pancreatic lipase inhibitors (e.g., orlistat); lipid-lowering agents (e.g., statins, fibrates, niacin or its derivatives (e.g., acipimox), lecithin, bile acid sequestrants, ezetimibe, lomitapide, phytosterols, omega-3 supplements, PCSK9 inhibitors); CB-1 antagonists; lipoxygenase inhibitors; somostatin analogs; insulin compounds or insulin analogs (e.g., human insulin, insulin lispro, insulin aspart, insulin glulisine, insulin glargine, insulin degludec); insulin sensitizers such as PPAR-γ agonists, PPAR-α agonists, or mixed PPAR-γ / α agonists (e.g., metformin, pioglitazone, or rosiglitazone); insulin secretagogues (e.g., nateglinide or repaglinide, or sulfonylureas such as gliclazide, glimeperide, limepiride, glyburide); SGLT2 inhibitors (e.g., dapagliflozin, canagliflozin, or empagliflozin); amylin analogs (e.g., pramlintide); DPPIV inhibitors (e.g., sitagliptin, saxagliptin, linagliptin, alogliptin, or vildagliptin); A compound or a pharmaceutically acceptable salt and / or solvate thereof for use, pharmaceutical composition for use, use, or method as described in claim 45 or claim 46, for use in combination with a GLP-1 agonist (e.g., albiglutide, dulaglutide, exenatide, liraglutide, semaglutide, or lixisenatide); an alpha-glucosidase inhibitor (e.g., acarbose, miglitol, or voglibose); a phosphodiesterase inhibitor (e.g., pentoxifylline); a glycogen phosphorylase inhibitor; an MCH-1 antagonist; a glucokinase activator; a glucagon antagonist; an insulin signaling agonist; a PTP1B inhibitor; a gluconeogenesis inhibitor; a GSK inhibitor; or a galanin receptor agonist.

64. Gastric or pancreatic lipase inhibitors (e.g., orlistat); lipid-lowering agents (e.g., statins, fibrates, niacin or its derivatives (e.g., acipimox), lecithin, bile acid sequestrants, ezetimibe, lomitapide, phytosterols, omega-3 supplements, PCSK9 inhibitors); CB-1 antagonists; lipoxygenase inhibitors; somostatin analogs; insulin compounds or insulin analogs (e.g., human insulin, insulin lispro, insulin aspart, insulin glulisine, insulin glargine, insulin degludec); insulin sensitizers such as PPAR-γ agonists, PPAR-α agonists, or mixed PPAR-γ / α agonists (e.g., metformin, pioglitazone, or rosiglitazone); insulin secretagogues (e.g., nateglinide or repaglinide, or sulfonylureas such as gliclazide, glimeperide, limepiride, glyburide); SGLT2 inhibitors (e.g., dapagliflozin, canagliflozin, or empagliflozin); amylin analogs (e.g., pramlintide); DPPIV inhibitors (e.g., sitagliptin, saxagliptin, linagliptin, alogliptin, or vildagliptin); 53. The compound for use, or a pharmaceutically acceptable salt and / or solvate thereof, pharmaceutical composition for use, use, or method according to any one of claims 47 to 52, for use in combination with a GLP-1 agonist (e.g., albiglutide, dulaglutide, exenatide, liraglutide, semaglutide, or lixisenatide); an alpha-glucosidase inhibitor (e.g., acarbose, miglitol, or voglibose); a phosphodiesterase inhibitor (e.g., pentoxifylline); a glycogen phosphorylase inhibitor; an MCH-1 antagonist; a glucokinase activator; a glucagon antagonist; an insulin signaling agonist; a PTP1B inhibitor; a gluconeogenesis inhibitor; a GSK inhibitor; or a galanin receptor agonist.

65. 2-((5-methoxypyridin-2-yl)methyl)-6-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)thio)phthalazin-1(2H)-one; 6-((1-(difluoromethyl)-1H-pyrazol-4-yl)thio)-2-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)methyl)phthalazin-1(2H)-one; 6-((1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazol-4-yl)thio)-2-((2,3-dihydrofuro[3,2-b]pyridin-5-yl)methyl)phthalazin-1(2H)-one; 2-((2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)methyl)-6-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)thio)phthalazin-1(2H)-one; 2-((2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)methyl)-6-((1-methyl-1H-pyrazol-4-yl)thio)phthalazin-1(2H)-one; and 2-((4-chloro-5-methyl-1H-pyrazol-3-yl)methyl)-6-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)sulfonyl)phthalazin-1(2H)-one; A compound selected from the group consisting of:

66. A method for preparing a compound of formula (Ia) or a salt thereof, such as a pharmaceutically acceptable salt and / or solvate thereof, according to any one of claims 1 to 19, comprising reacting a compound of formula (IIa): 【Chemistry 26】 or a salt and / or solvate thereof; Oxidizing with an oxidizing agent such as oxone Includes; where R A and R B as defined in any one of claims 1 to 19.

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